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David E Jane - One of the best experts on this subject based on the ideXlab platform.
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Antagonism of recombinant and native GluK3-containing Kainate Receptors
Neuropharmacology, 2008Co-Authors: David Perrais, David E Jane, Paulo S. Pinheiro, Christophe MulleAbstract:A number of Kainate Receptor Antagonists have shown selectivity for Receptors containing the GluK1 subunit. Here, we analyze the effects of these GluK1 Antagonists on currents mediated by recombinant homomeric GluK3 and heteromeric GluK2/3 Receptors expressed in HEK 293 cells and activated by fast application of glutamate. We show that, amongst these compounds, UBP302, UBP310 and UBP316 effectively block recombinant homomeric GluK3 Receptors. However, these Antagonists are ineffective in blocking homomeric GluK2 or heteromeric GluK2/3 Receptors. In addition, these Antagonists do not affect presynaptic Kainate Receptors at mouse hippocampal mossy fibre synapses, which are thought to be composed of GluK2 and GluK3 subunits. Moreover, the AMPA Receptor-selective non-competitive antagonist GYKI 53655 blocks, at high concentrations, GluK3-containing Receptors and decreases short-term plasticity at mossy fibre synapses. These results expand the range of targets of Kainate Receptor Antagonists and provide pharmacological tools to study the elusive mechanisms of neurotransmitter control by presynaptic Kainate Receptors.
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Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 Kainate Receptor Antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Nigel P Dolman, Julia C A More, Jody L Knauss, David Bleakman, Graham L Collingridge, Andrew Alt, Olli T. Pentikäinen, Carla Glasser, Mark L. Mayer, David E JaneAbstract:Some N3-substituted analogues of willardiine such as 11 and 13 are selective Kainate Receptor Antagonists. In an attempt to improve the potency and selectivity for Kainate Receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing Kainate Receptors (KB values of 7 ± 1 and 5 ± 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 μM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.
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structure activity relationship studies on n3 substituted willardiine derivatives acting as ampa or Kainate Receptor Antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Nigel P Dolman, Julia C A More, Helen M Troop, Jody L Knauss, David Bleakman, Graham L Collingridge, David E JaneAbstract:N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and Kainate Receptor Antagonists. In an attempt to improve the potency and selectivity of these AMPA and Kainate Receptor Antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing Kainate Receptors (KD 0.105 ± 0.007 μM vs Kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5-fluorowillardiine on native AMPA Receptors). On recombinant human GLUK5, GLUK5/GLUK6, and GLUK5/GLUK2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 Kainate Receptors or homomeric GLUA1-4 AMPA Receptors (IC50 values > 100 μM). Thus, 43 is a po...
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structural requirements for novel willardiine derivatives acting as ampa and Kainate Receptor Antagonists
British Journal of Pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
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Structural requirements for novel willardiine derivatives acting as AMPA and Kainate Receptor Antagonists
British journal of pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
Julia C A More - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 Kainate Receptor Antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Nigel P Dolman, Julia C A More, Jody L Knauss, David Bleakman, Graham L Collingridge, Andrew Alt, Olli T. Pentikäinen, Carla Glasser, Mark L. Mayer, David E JaneAbstract:Some N3-substituted analogues of willardiine such as 11 and 13 are selective Kainate Receptor Antagonists. In an attempt to improve the potency and selectivity for Kainate Receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing Kainate Receptors (KB values of 7 ± 1 and 5 ± 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 μM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.
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structure activity relationship studies on n3 substituted willardiine derivatives acting as ampa or Kainate Receptor Antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Nigel P Dolman, Julia C A More, Helen M Troop, Jody L Knauss, David Bleakman, Graham L Collingridge, David E JaneAbstract:N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and Kainate Receptor Antagonists. In an attempt to improve the potency and selectivity of these AMPA and Kainate Receptor Antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing Kainate Receptors (KD 0.105 ± 0.007 μM vs Kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5-fluorowillardiine on native AMPA Receptors). On recombinant human GLUK5, GLUK5/GLUK6, and GLUK5/GLUK2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 Kainate Receptors or homomeric GLUA1-4 AMPA Receptors (IC50 values > 100 μM). Thus, 43 is a po...
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structural requirements for novel willardiine derivatives acting as ampa and Kainate Receptor Antagonists
British Journal of Pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
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Structural requirements for novel willardiine derivatives acting as AMPA and Kainate Receptor Antagonists
British journal of pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
Nigel P Dolman - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 Kainate Receptor Antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Nigel P Dolman, Julia C A More, Jody L Knauss, David Bleakman, Graham L Collingridge, Andrew Alt, Olli T. Pentikäinen, Carla Glasser, Mark L. Mayer, David E JaneAbstract:Some N3-substituted analogues of willardiine such as 11 and 13 are selective Kainate Receptor Antagonists. In an attempt to improve the potency and selectivity for Kainate Receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing Kainate Receptors (KB values of 7 ± 1 and 5 ± 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 μM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.
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structure activity relationship studies on n3 substituted willardiine derivatives acting as ampa or Kainate Receptor Antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Nigel P Dolman, Julia C A More, Helen M Troop, Jody L Knauss, David Bleakman, Graham L Collingridge, David E JaneAbstract:N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and Kainate Receptor Antagonists. In an attempt to improve the potency and selectivity of these AMPA and Kainate Receptor Antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing Kainate Receptors (KD 0.105 ± 0.007 μM vs Kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5-fluorowillardiine on native AMPA Receptors). On recombinant human GLUK5, GLUK5/GLUK6, and GLUK5/GLUK2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 Kainate Receptors or homomeric GLUA1-4 AMPA Receptors (IC50 values > 100 μM). Thus, 43 is a po...
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structural requirements for novel willardiine derivatives acting as ampa and Kainate Receptor Antagonists
British Journal of Pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
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Structural requirements for novel willardiine derivatives acting as AMPA and Kainate Receptor Antagonists
British journal of pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
P M Headley - One of the best experts on this subject based on the ideXlab platform.
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Studies of synaptic transmission in vivo: indirect versus direct effects of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid/Kainate Antagonists on rat spinal sensory responses.
Neuroscience letters, 1996Co-Authors: M J Cumberbatch, J F Herrero, P M HeadleyAbstract:The (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/Kainate Receptor Antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) were examined by microiontophoretic administration in electrophysiological tests on spinal neurones in alpha-chloralose anaesthetized rats. The Antagonists significantly reduced extracellularly recorded nociceptive and non-nociceptive responses, as expected; concurrently they reduced background discharge. When the background discharge rate was held constant, the Antagonists no longer significantly reduced the evoked responses. This indicates that in the absence of such control, the Antagonists decreased cell excitability and only indirectly affected the test responses. Unless such indirect effects have been controlled for, the interpretation of the actions of AMPA/Kainate Antagonists on evoked synaptic responses is compromised and may be erroneous.
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Studies of synaptic transmission in vivo: indirect versus direct effects of (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid/Kainate Antagonists on rat spinal sensory responses
Neuroscience Letters, 1996Co-Authors: M J Cumberbatch, J F Herrero, P M HeadleyAbstract:Abstract The (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/Kainate Receptor Antagonists 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo [ƒ]quinoxaline (NBQX) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) were examined by microiontophoretic administration in electrophysiological tests on spinal neurones in α-chloralose anaesthetized rats. The Antagonists significantly reduced extracellularly recorded nociceptive and non-nociceptive responses, as expected; concurrently they reduced background discharge. When the background discharge rate was held constant, the Antagonists no longer significantly reduced the evoked responses. This indicates that in the absence of such control, the Antagonists decreased cell excitability and only indirectly affected the test responses. Unless such indirect effects have been controlled for, the interpretation of the actions of AMPA/Kainate Antagonists on evoked synaptic responses is compromised and may be erroneous.
Helen M Troop - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship studies on n3 substituted willardiine derivatives acting as ampa or Kainate Receptor Antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Nigel P Dolman, Julia C A More, Helen M Troop, Jody L Knauss, David Bleakman, Graham L Collingridge, David E JaneAbstract:N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and Kainate Receptor Antagonists. In an attempt to improve the potency and selectivity of these AMPA and Kainate Receptor Antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing Kainate Receptors (KD 0.105 ± 0.007 μM vs Kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5-fluorowillardiine on native AMPA Receptors). On recombinant human GLUK5, GLUK5/GLUK6, and GLUK5/GLUK2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 Kainate Receptors or homomeric GLUA1-4 AMPA Receptors (IC50 values > 100 μM). Thus, 43 is a po...
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structural requirements for novel willardiine derivatives acting as ampa and Kainate Receptor Antagonists
British Journal of Pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
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Structural requirements for novel willardiine derivatives acting as AMPA and Kainate Receptor Antagonists
British journal of pharmacology, 2003Co-Authors: Julia C A More, Helen M Troop, Nigel P Dolman, David E JaneAbstract:The natural product willardiine is an AMPA Receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and Kainate Receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the Antagonists at AMPA or Kainate Receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA Receptor antagonist activity. To examine antagonist activity at Kainate Receptors, the ability of compounds to depress Kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and Kainate Receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA Receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 μM, respectively). For Kainate Receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root Kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 μM, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at Kainate Receptors (UBP291 and UBP301 antagonised Kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 μM, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ∼30-fold selective Kainate Receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated Kainate response. Keywords: Neonatal rat spinal cord, willardiine, 3-CBW (UBP282), UBP301, Kainate, AMPA, antagonist Introduction Ionotropic glutamate Receptors in the mammalian central nervous system have been divided into three main types–NMDA, AMPA and Kainate Receptors–depending on their pharmacology (for comprehensive reviews see Jane et al., 2000; Jane, 2002). AMPA Receptors are made up from a combination of GluR1–4 subunits, while Kainate Receptors consist of a combination of GluR5–7, KA1 and KA2 subunits (Bleakman & Lodge, 1998). Although selective AMPA Receptor Antagonists are available, few discriminate between individual subunits and selective Kainate Receptor Antagonists remain scarce (for reviews see Chittajallu et al., 1999; Jane et al., 2000). Recently, a number of decahydroisoquinoline analogues have been shown to be GluR5-selective Antagonists. These compounds have been used to show that GluR5-selective Antagonists may have utility in the treatment of neuropathic pain (Simmons et al., 1998), cerebral ischaemia (O'Neill et al., 1998) and epilepsy (Smolders et al., 2002). The natural product willardiine acts as an agonist at AMPA Receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5-containing Kainate Receptors depending on the nature of the 5-substituent on the uracil ring (Evans et al., 1980; Patneau et al., 1992; Wong et al., 1994; Jane et al., 1997). For example, (S)-5-iodowillardiine is a highly selective GluR5 agonist whereas (S)-5-fluorowillardiine is an AMPA Receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al., 1997; Thomas et al., 1998; Varney et al., 1998). A number of studies have demonstrated the conversion of glutamate Receptor agonists into Antagonists by extending the chain length between the α-carboxylic acid and the terminal acidic group (Davies et al., 1982; Krogsgaard-Larsen et al., 1991; Madsen et al., 1996; Jane et al., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and Kainate Receptors by increasing the interacidic group chain length when it was shown that 3-CBW ((S)-3-(4-carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA Receptors on motor neurones and Kainate Receptors on dorsal root C-fibres (More et al., 2002a, b). The aim of the current study was to investigate the structural changes required to convert willardiine into an antagonist and to find ways of increasing the potency of antagonism and the selectivity towards either AMPA or Kainate Receptors. To achieve this, several derivatives of willardiine have been assessed for their antagonist activity at AMPA and Kainate Receptors. In order to investigate whether adding a substituent to the N3-position is sufficient to convert willardiine into an antagonist, we synthesized the 3-methyl analogue ((S)-3-methylwillardiine, UBP294). Other structural changes made to the willardiine structure included changing the stereochemistry at the stereogenic centre, changing the interacidic group chain length and adding substituents to the 5-position of the uracil ring. Thus, the following compounds were investigated for their AMPA and/or Kainate Receptor antagonist activity (see Figure 1 for structures): (S)-3-carboxymethylwillardiine (UBP275), (R)-3-carboxymethylwillardiine (UBP276), (S)-3-(2-carboxyethyl)willardiine (UBP277), (R)-3-(2-carboxyethyl)willardiine (UBP278), (S)-3-(3-carboxypropyl)willardiine (UBP279), (R)-3-(3-carboxypropyl)willardiine (UBP280), (S)-3-methylwillardiine (UBP294), (S)-1-carboxymethyl-5-methylwillardiine (UBP293), (S)-1-carboxymethylwillardiine (UBP281), (S)-3-(2-carboxyethyl)-5-nitrowillardiine (UBP290), (S)-3-(2-carboxyethyl)-5-iodowillardiine (UBP291) and (S)-3-(4-carboxybenzyl)-5-iodowillardiine (UBP301). Figure 1 Structure of willardiine and a number of new derivatives. To compare the Antagonists for activity at AMPA Receptors, their ability to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR-VRP has been shown to be evoked by the stimulation of AMPA Receptors and can therefore be used as a convenient method to compare AMPA Receptor Antagonists using native Receptors (More et al., 2002b). To investigate the ability of the novel compounds to antagonise Kainate Receptors, their ability to depress Kainate-induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly Kainate Receptors of the GluR5 subtype (Bettler et al., 1990; Partin et al., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective Kainate Receptor Antagonists using a native Receptor population (Agrawal & Evans, 1986; Thomas et al., 1998; More et al., 2002a, b). As there are a limited number of selective Antagonists available for AMPA and Kainate Receptors, it is important to discover new families of compounds that have the potential to be used as Antagonists. Small changes in substituents can have drastic selectivity effects in willardiine derivatives acting as agonists, as highlighted by (S)-5-iodowillardiine and (S)-5-fluorowillardiine. It is therefore possible that careful structure–activity analysis of willardiine derivatives may lead to novel selective and potent Antagonists for either AMPA or Kainate Receptors. Preliminary reports of this work have been published (More et al., 2001; More et al., 2002a).
