The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform
C.j. Carter - One of the best experts on this subject based on the ideXlab platform.
-
The pharmacology of native N-methtl-D-aspartate receptor subtypes: Different receptors control the release of different striatal and spinal transmitters
Progress in neuro-psychopharmacology & biological psychiatry, 1998Co-Authors: Masahiro Nankai, Marijan Klarica, Dominique Fage, C.j. CarterAbstract:Abstract 1. 1. N-methyl-D-aspartate (NMDA) increases the release of radiolabelled dopamine, GABA, acetylcholine and spermidine from rat striatal slices and of noradrenaline from the dorsal cervical spinal cord. 2. 2. These five responses show differing sensitivities to NMDA and also to a variety of competitive Antagonists, NMDA channel blockers, Glycine Antagonists and polyamine site Antagonists. 3. 3. Inhibitory activity profiles for 20 different Antagonists are presented. All compounds tested showed some degree of selectivity with regard to the different responses and each response showed particular characteristics that suggested mediation by a particular native NMDA receptor subtype. 4. 4 Receptors controlling dopamine, GABA and noradrenaline release were generally more sensitive to most Antagonists compared to those controlling acetylcholine and spermidine release. 5. 5. Receptors controlling spermidine release were furthermore insensitive to magnesium, argiotoxin, ifenprodil and eliprodil and displayed low sensitivity to memantine, dextrorphan and dextromethorphan. 6. 6. Receptors controlling noradrenaline release could be further discriminated from those controlling dopamine and GABA release by very high sensitivity to magnesium and MK-801 and to the Glycine antagonist L-689,560 but not to other Glycine Antagonists (CNQX, DNQX, 7-Chlorokynurenate, HA-966). 7. 7. Many other individual drug or receptor differences were noted. The different profiles observed suggest a wide diversity of native NMDA receptors with different properties and an unexpectedly rich pharmacopeia of subtype selective Antagonists of native NMDA receptors. 8. 8. Matching subtype selectivity to particular behavioural effects may be possible and the design of subtype selective NMDA Antagonists for particular clinical applications while avoiding side effect generation seems to be feasible.
-
Evidence for native NMDA receptor subtype pharmacology as revealed by differential effects on the NMDA-evoked release of striatal neuromodulators: Eliprodil, ifenprodil and other native NMDA receptor subtype selective compounds
Neurochemistry international, 1996Co-Authors: Masahiro Nankai, Marijan Klarica, Dominique Fage, C.j. CarterAbstract:NMDA increases the release of [14C]acetylcholine and [3H]spermidine or of [14C]GABA and [3H]dopamine from rat striatal slices. The pharmacology of these responses suggests that release of dopamine and GABA, acetylcholine, and spermidine is mediated, respectively, by three distinct NMDA receptor subtypes. IC50 values of compounds for the inhibition of dopamine and GABA release were closely matched, suggesting mediation by the same subtype. This receptor was generally more sensitive to all NMDA Antagonists tested relative to that controlling acetylcholine or spermidine release (channel blockers, Glycine Antagonists, competitive Antagonists and polyamine Antagonists). The receptors controlling acetylcholine and spermidine release were characterised by lower antagonist sensitivity in general, and that controlling spermidine release was further defined by a marked insensitivity to ifenprodil, eliprodil, magnesium, dextromethorphan, dextrorphan, memantine, desipramine and polyamine spider toxins. In binding studies in which the displacement of 2 nM [3H]MK801 was studied in membranes prepared from a number of brain regions (in the presence of saturating concentrations of glutamate, Glycine and spermidine) small regional differences in IC50 values were observed for a number of channel blockers, but no compound generated biphasic displacement curves that would allow masking of a particular subtype and it was not possible to detect binding components that were insensitive to memantine, dextrorphan dextromethorphan or desipramine. Ifenprodil produced biphasic displacement curves in the 1-day-old rat cortex and midbrain (with IC50 values of approximately 2 and 70 microM) and both ifenprodil and eliprodil displaced a small proportion (18%) of [3H]MK-801 with high affinity in the adult rat spinal cord. Displacement of [3H]MK801 by these compounds in all other adult brain regions (cortex, striatum, hippocampus, thalamus, pons, medulla, cerebellum) was monophasic and of low affinity. In general the subtype selectivity suggested by the release studies was not mirrored in the binding experiments, probably because of excessive heterogeneity of sites in the membrane preparations and to the subtype selectivity of [3H]MK801 itself.
-
synergism between the nmda receptor antagonistic effects of ifenprodil and the Glycine antagonist 7 chlorokynurenate in vivo
European Journal of Pharmacology, 1994Co-Authors: Carole Voltz, Dominique Fage, C.j. CarterAbstract:Abstract Ifenprodil (30 mg/kg i.p.) when administered alone did not antagonise the stimulatory effects of intrastriatally administered N- methyl - D - aspartate (NMDA: 500 μM, via a dialysis fibre) on spermine or spermidine release. The effects of NMDA were antagonised by the intrastriatal co-infusion of the Glycine site antagonist, 7-chlorokynurenate (100 μM). Lower concentrations of 7-chlorokynurenate (3 μM) were without effect on the NMDA response. In the presence of a subthreshold concentration of striatally infused 7-chlorokynurenate (3 μM), systematically administered ifenprodil (30 mg/kg i.p.) blocked the effects of NMDA on polyamine release and also potentiated the inhibitory effects of 30 μM 7-chlorokynurenate. These results demonstrate that synergism between Glycine Antagonists and polyamine Antagonists, as previously observed in vitro, is also observed in vivo.
Fabrizio Micheli - One of the best experts on this subject based on the ideXlab platform.
-
New Synthesis of Substituted 2‐Carboxyindole Derivatives: Versatile Introduction of a Carbamoylethynyl Moiety at the C‐3‐Position.
ChemInform, 2010Co-Authors: Cheryl T. Hewkin, Fabrizio Micheli, Romano Di Fabio, Alfredo Cugola, Paola Gastaldi, Nadia Conti, Anna M. QuagliaAbstract:A novel series of 3-carbamoylethynyl-2-carboxyindoles, Antagonists acting at the strychnine-insensitive Glycine binding site associated with the NMDA receptor, has been synthesised. This new versatile approach involves the introduction of a 2-chloroethenyl moiety in position C-3 with subsequent derivatisation of the terminal carboxyl group, followed by an unusual elimination of HCl to afford the ethynyl functionality. This novel series of Glycine Antagonists was evaluated in terms of in vitro affinity at the Glycine binding site and the most potent compound was tested in vivo in the NMDA-induced convulsions model in mice.
-
Synthesis and pharmacological characterisation of a conformationally restrained series of indole-2-carboxylates as in vivo potent Glycine Antagonists.
Farmaco (Societa chimica italiana : 1989), 2001Co-Authors: Romano Di Fabio, Daniele Donati, Fabrizio Micheli, Alfredo Cugola, Gianluca Araldi, Davide Baraldi, Paola Gastaldi, Simone Giacobbe, Giorgio PentassugliaAbstract:After the identification of GV150526, the indole-2-carboxylate template was further explored in order to identify novel potential anti-stroke agents. In particular, the SAR of the side chain present at the C-3 position of the indole nucleus was widely studied. In this paper, the synthesis and the pharmacological profile of a further class of conformationally restricted analogues of GV150526 as in vitro and in vivo potent Glycine Antagonists is reported. In particular, a pyrazolidinone derivative was identified as a potent neuroprotective agent in animal models of cerebral ischaemia.
-
Recent developments in Glycine Antagonists
Expert Opinion on Therapeutic Patents, 2000Co-Authors: Daniele Donati, Fabrizio MicheliAbstract:The analysis of patents published on Glycine Antagonists over the last four years sheds a quite interesting light on a complex picture, revealing the interest towards a few classes of Antagonists. A detailed report on these new molecules is presented here.
-
New synthesis of substituted 2-carboxyindole derivatives: versatile introduction of a carbamoylethynyl moiety at the C-3 position.
Archiv der Pharmazie, 1999Co-Authors: Cheryl T. Hewkin, Fabrizio Micheli, Romano Di Fabio, Alfredo Cugola, Paola Gastaldi, Nadia Conti, Anna M. QuagliaAbstract:A novel series of 3-carbamoylethynyl-2-carboxyindoles, Antagonists acting at the strychnine-insensitive Glycine binding site associated with the NMDA receptor, has been synthesised. This new versatile approach involves the introduction of a 2-chloroethenyl moiety in position C-3 with subsequent derivatisation of the terminal carboxyl group, followed by an unusual elimination of HCl to afford the ethynyl functionality. This novel series of Glycine Antagonists was evaluated in terms of in vitro affinity at the Glycine binding site and the most potent compound was tested in vivo in the NMDA-induced convulsions model in mice.
-
synthesis and biological evaluation of pyrido 2 3 b pyrazine and pyrido 2 3 b pyrazine n oxide as selective Glycine Antagonists
ChemInform, 1997Co-Authors: Alfredo Cugola, Daniele Donati, Fabrizio Micheli, Angelo Reggiani, Andrea Missio, Angelo Pecunioso, Giorgio Tarzia, M Guarneri, V ZaniratoAbstract:Abstract Pyrido[2,3-b]pyrazines and pyrido[2,3-b]purazines-N-oxides have been synthesized and evaluated for in vitro/in vivo antagonistic activity at the Glycine site on the NMDA receptor
Ryu Nagata - One of the best experts on this subject based on the ideXlab platform.
-
Enzymatic Resolution of 2-Substituted Tetrahydroquinolines. Convenient Approaches to Tricyclic Quinoxalinediones as Potent NMDA-Glycine Antagonists.
ChemInform, 2010Co-Authors: Seiji Katayama, Ryu NagataAbstract:Abstract Two approaches leading to the enantiomerically pure tricyclic quinoxalinedione class of NMDA-Glycine Antagonists using enzymatic resolutions are described. An intermediate, racemic methyl 1,2,3,4-tetrahydroquinoline-2-carboxylate 3 , was resolved to ( S )- 3 in 97% ee and 47% yield (E=67) using α-chymotrypsin. In an improved method, hydrolysis of another intermediate, racemic methyl 1,2,3,4-tetrahydroquinoline-2-acetate 4 , with Novozym ® 435 provided the desired ( S )- 4 in high enantioselectivity and yield (93% ee, 50%, E=94).
-
Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists
Current topics in medicinal chemistry, 2006Co-Authors: Ryu Nagata, Seiji Katayama, Ken-ichi Ohtani, Hiroyasu Tanaka, Kozo ShimagoAbstract:This review article describes the development of in vivo active Antagonists for the Glycine binding site of the NMethyl- D-Aspartate (NMDA) receptor. There were several difficulties in identifying a class of Antagonists with in vivo efficacy and only a few compounds succeeded in emerging with activity in vivo. A series of tricyclic quinoxalinediones was highly potent Glycine Antagonists in vitro and the derivatives having a zwitterionic moiety including SM-18400 indeed showed in vivo activity. Similarly, tricyclic indole-2-carboxylic acids having a zwitterionic moiety such as SM- 31900 were also active in vivo. In fact, SM-18400 and SM-31900 exhibited efficacy in several animal stroke models using intravenous infusion protocols. The practical syntheses of SM-18400 and SM-31900 as well as the novel synthesis of moderately active Glycine Antagonists, tricyclic azakynurenic acids, were also developed.
-
Synthesis of Tricyclic Indole-2-caboxylic Acids as Potent NMDA-Glycine Antagonists
The Journal of organic chemistry, 2001Co-Authors: Seiji Katayama, Ryu NagataAbstract:The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-Glycine Antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig−Horner−Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (...
-
tricyclic quinoxalinediones 5 6 dihydro 1h pyrrolo 1 2 3 de quinoxaline 2 3 diones and 6 7 dihydro 1h 5h pyrido 1 2 3 de quinoxaline 2 3 diones as potent Antagonists for the Glycine binding site of the nmda receptor
Journal of Medicinal Chemistry, 1994Co-Authors: Ryu Nagata, N Tanno, Toru Kodo, H Yamaguchi, T Nishimura, F Antoku, T Tatsuno, T Kato, Y TanakaAbstract:A series of tricyclic quinoxalinediones, 5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-diones and 6,7-dihydro-1H,5H-pyrido[1,2,3-de]quinoxaline-2,3-diones, were synthesized and was evaluated for their affinity for the Glycine binding site of the NMDA receptor using a [3H]-5,7-dichlorokynurenic acid binding assay. The six-membered ring-fused tricyclic quinoxalinedione 18g (Ki = 9.9 nM) displayed high affinity for the Glycine site. The anilide derivative 20g (Ki = 2.6 nM) was 4-fold more potent than 18g and as potent as L-689,560, one of the most potent Glycine Antagonists so far prepared. Although the carboxylic acid derivative of the corresponding five-membered ring-fused tricyclic quinoxalinedione 18e (Ki = 7.3 nM) had affinity comparable to that of 18g, the anilide derivative 20e largely decreased in the affinity in contrast to 20g. Enantiomers 23g, 24g, 25g, and 26g were prepared and tested. Only the S enantiomer 25g (Ki = 0.96 nM) retained the affinity among the anilide derivatives, whereas both enantiomers 23g (Ki = 2.3 nM) and 24g (Ki = 9.6 nM) were active among the carboxylic acid derivatives. The origin of the high affinity of carboxylic acid derivatives such as 18e and 18g would be a charge-charge interaction between the anionic carboxylate residues of the compounds and the cationic proton-donor site in the receptor.
Daniele Donati - One of the best experts on this subject based on the ideXlab platform.
-
Synthesis and pharmacological characterisation of a conformationally restrained series of indole-2-carboxylates as in vivo potent Glycine Antagonists.
Farmaco (Societa chimica italiana : 1989), 2001Co-Authors: Romano Di Fabio, Daniele Donati, Fabrizio Micheli, Alfredo Cugola, Gianluca Araldi, Davide Baraldi, Paola Gastaldi, Simone Giacobbe, Giorgio PentassugliaAbstract:After the identification of GV150526, the indole-2-carboxylate template was further explored in order to identify novel potential anti-stroke agents. In particular, the SAR of the side chain present at the C-3 position of the indole nucleus was widely studied. In this paper, the synthesis and the pharmacological profile of a further class of conformationally restricted analogues of GV150526 as in vitro and in vivo potent Glycine Antagonists is reported. In particular, a pyrazolidinone derivative was identified as a potent neuroprotective agent in animal models of cerebral ischaemia.
-
Recent developments in Glycine Antagonists
Expert Opinion on Therapeutic Patents, 2000Co-Authors: Daniele Donati, Fabrizio MicheliAbstract:The analysis of patents published on Glycine Antagonists over the last four years sheds a quite interesting light on a complex picture, revealing the interest towards a few classes of Antagonists. A detailed report on these new molecules is presented here.
-
Synthesis and pharmacological properties of novel Glycine Antagonists.
Pharmaceutica acta Helvetiae, 2000Co-Authors: Daniele Donati, R Di FabioAbstract:The NMDA receptor is an ionotropic receptor complex widely distributed in the central nervous system and its activation, particularly in hypoxic conditions such as stroke, traumatic head injury and hypoglycemia, results in a massive influx of calcium ions into the post-synaptic neurones, leading to cell death through the activation of several neurotoxic cascades. The NMDA receptor is a unique ionotropic receptor complex because its activation requires the simultaneous binding of glutamate and Glycine and selective Antagonists at the Glycine binding site are endowed with a better side-effect profile than competitive NMDA Antagonists. Then, considerable efforts have been devoted to find potent and selective ligands, resulting in the identification of several classes of Glycine Antagonists. The research at Glaxo Wellcome has been aimed at the identification of novel in vivo active Glycine Antagonists, and led to the synthesis and pharmacological characterization of a number of novel, potent and systemically active compounds belonging to different chemical classes.
-
synthesis and biological evaluation of pyrido 2 3 b pyrazine and pyrido 2 3 b pyrazine n oxide as selective Glycine Antagonists
ChemInform, 1997Co-Authors: Alfredo Cugola, Daniele Donati, Fabrizio Micheli, Angelo Reggiani, Andrea Missio, Angelo Pecunioso, Giorgio Tarzia, M Guarneri, V ZaniratoAbstract:Abstract Pyrido[2,3-b]pyrazines and pyrido[2,3-b]purazines-N-oxides have been synthesized and evaluated for in vitro/in vivo antagonistic activity at the Glycine site on the NMDA receptor
-
Novel Glycine Antagonists as potent neuroprotective agents
Pharmacochemistry Library, 1997Co-Authors: Giovanni Gaviraghi, Daniele Donati, Aldo Feriani, Romano Di Fabio, Alfredo Cugola, Emiliangelo Ratti, David G. Trist, Angelo ReggianiAbstract:Publisher Summary This chapter discusses novel Glycine Antagonists as potent neuroprotective agents. Stroke is an abrupt onset of neurological conditions caused by an insufficient cerebral circulation (ischaemic or emorragic). When blood flow is reduced, neuronal cells are deprived of the necessary oxygen supply leading to rapid brain damaged (necrosis). In ischaemic conditions, the reduction of the oxygen–energy supply to the cells causes a significant increase of glutamate within the synaptic cleft. Screening cascade includes (1) binding assay to evaluate the affinity for the Glycine site and selectivity for glutamate receptors, (2) in vitro functional antagonism studies to evaluate potency and activity, (3) in vivo anticonvulsant activity in mice, (4) in vivo models of stroke in rats (MCAo). Functional antagonism at the Glycine binding site is demonstrated by the ability of new chemical entities (NCE) to antagonize the Glycine-induced enhancement of the binding of the channel blocking agent [ 3 H]TCP in a Glycine-sensitive extensively washed rat cortical preparation. The assessment of the neuroprotective activity in stroke model, both pre and post-ischemia, is carried out using the permanent occlusion of the middle cerebral artery (MCA) in rats.
Masahiro Nankai - One of the best experts on this subject based on the ideXlab platform.
-
The pharmacology of native N-methtl-D-aspartate receptor subtypes: Different receptors control the release of different striatal and spinal transmitters
Progress in neuro-psychopharmacology & biological psychiatry, 1998Co-Authors: Masahiro Nankai, Marijan Klarica, Dominique Fage, C.j. CarterAbstract:Abstract 1. 1. N-methyl-D-aspartate (NMDA) increases the release of radiolabelled dopamine, GABA, acetylcholine and spermidine from rat striatal slices and of noradrenaline from the dorsal cervical spinal cord. 2. 2. These five responses show differing sensitivities to NMDA and also to a variety of competitive Antagonists, NMDA channel blockers, Glycine Antagonists and polyamine site Antagonists. 3. 3. Inhibitory activity profiles for 20 different Antagonists are presented. All compounds tested showed some degree of selectivity with regard to the different responses and each response showed particular characteristics that suggested mediation by a particular native NMDA receptor subtype. 4. 4 Receptors controlling dopamine, GABA and noradrenaline release were generally more sensitive to most Antagonists compared to those controlling acetylcholine and spermidine release. 5. 5. Receptors controlling spermidine release were furthermore insensitive to magnesium, argiotoxin, ifenprodil and eliprodil and displayed low sensitivity to memantine, dextrorphan and dextromethorphan. 6. 6. Receptors controlling noradrenaline release could be further discriminated from those controlling dopamine and GABA release by very high sensitivity to magnesium and MK-801 and to the Glycine antagonist L-689,560 but not to other Glycine Antagonists (CNQX, DNQX, 7-Chlorokynurenate, HA-966). 7. 7. Many other individual drug or receptor differences were noted. The different profiles observed suggest a wide diversity of native NMDA receptors with different properties and an unexpectedly rich pharmacopeia of subtype selective Antagonists of native NMDA receptors. 8. 8. Matching subtype selectivity to particular behavioural effects may be possible and the design of subtype selective NMDA Antagonists for particular clinical applications while avoiding side effect generation seems to be feasible.
-
Evidence for native NMDA receptor subtype pharmacology as revealed by differential effects on the NMDA-evoked release of striatal neuromodulators: Eliprodil, ifenprodil and other native NMDA receptor subtype selective compounds
Neurochemistry international, 1996Co-Authors: Masahiro Nankai, Marijan Klarica, Dominique Fage, C.j. CarterAbstract:NMDA increases the release of [14C]acetylcholine and [3H]spermidine or of [14C]GABA and [3H]dopamine from rat striatal slices. The pharmacology of these responses suggests that release of dopamine and GABA, acetylcholine, and spermidine is mediated, respectively, by three distinct NMDA receptor subtypes. IC50 values of compounds for the inhibition of dopamine and GABA release were closely matched, suggesting mediation by the same subtype. This receptor was generally more sensitive to all NMDA Antagonists tested relative to that controlling acetylcholine or spermidine release (channel blockers, Glycine Antagonists, competitive Antagonists and polyamine Antagonists). The receptors controlling acetylcholine and spermidine release were characterised by lower antagonist sensitivity in general, and that controlling spermidine release was further defined by a marked insensitivity to ifenprodil, eliprodil, magnesium, dextromethorphan, dextrorphan, memantine, desipramine and polyamine spider toxins. In binding studies in which the displacement of 2 nM [3H]MK801 was studied in membranes prepared from a number of brain regions (in the presence of saturating concentrations of glutamate, Glycine and spermidine) small regional differences in IC50 values were observed for a number of channel blockers, but no compound generated biphasic displacement curves that would allow masking of a particular subtype and it was not possible to detect binding components that were insensitive to memantine, dextrorphan dextromethorphan or desipramine. Ifenprodil produced biphasic displacement curves in the 1-day-old rat cortex and midbrain (with IC50 values of approximately 2 and 70 microM) and both ifenprodil and eliprodil displaced a small proportion (18%) of [3H]MK-801 with high affinity in the adult rat spinal cord. Displacement of [3H]MK801 by these compounds in all other adult brain regions (cortex, striatum, hippocampus, thalamus, pons, medulla, cerebellum) was monophasic and of low affinity. In general the subtype selectivity suggested by the release studies was not mirrored in the binding experiments, probably because of excessive heterogeneity of sites in the membrane preparations and to the subtype selectivity of [3H]MK801 itself.