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William A. Denny - One of the best experts on this subject based on the ideXlab platform.
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Homobivalent Conjugation Increases the Allosteric Effect of 9-Aminoacridine at the α1-Adrenergic Receptors
2016Co-Authors: Adrian P. Campbell, William A. Denny, Laurence P. G. Wakelin, Angela M. FinchAbstract:The α1-adrenergic receptors are targets for a number of cardiovascular and central nervous system conditions, but the current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1-adrenergic ligands, yet there is little information describing this drug class at the α1-adrenergic receptors. We have identified a series of 9-Aminoacridine compounds that demonstrate allosteric modulation of the α1A- and α1B-adrenergic receptors. The 9-Aminoacridines increase the rate of [3H]prazosin dissociation from the α1A- and α1B-adrenergic receptors and noncompetitively inhibit receptor activation by the endogenous agonist norepinephrine. The structurally similar compound, tacrine, which is a known allosteric modulator of the muscarinic receptors, is also shown to be a modulator of the α1-adrenergic receptors, which suggests a general lack of selectivity for allosteric binding sites across aminergic G protein-coupled receptor. Conjugation of two 9-Aminoacridine pharmacophores, using linkers of varying length, increases the potency and efficacy of the allosteric effects of this ligand, likely through optimization of bitopic engagement of the allosteric and orthosteric binding sites of the receptor. Such a bivalent approach may provide a mechanism for fine tuning the efficacy of allosteric compounds in future drug design efforts.
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The interaction of DNA-targeted 9-Aminoacridine-4-carboxamide platinum complexes with DNA in intact human cells.
2002Co-Authors: Mark D. Temple, W. David Mcfadyen, Rodney J. Holmes, Patsy Recabarren, William A. DennyAbstract:Abstract As part of an ongoing drug development programme, this paper describes the sequence specificity and time course of DNA adduct formation for a series of novel DNA-targeted analogues of cis-diaminedichloroplatinum(II) (cisplatin) (9-Aminoacridine-4-carboxamide Pt complexes) in intact HeLa cells. The sequence specificity of DNA damage caused by cisplatin and analogues in human (HeLa) cells was studied using Taq DNA polymerase and a linear amplification/polymerase stop assay. Primer extension is inhibited by a Pt–DNA adduct, and hence the sites of these lesions can be analysed on DNA sequencing gels. The repetitive alphoid DNA sequence was used as the target DNA in human cells. The 9-Aminoacridine-4-carboxamide Pt complexes exhibited a markedly different sequence specificity relative to cisplatin and other analogues. The sequence specificity of the 9-Aminoacridine-4-carboxamide Pt complexes is shifted away from a preference for runs of guanines. The 9-Aminoacridine-4-carboxamide Pt complexes have an enhanced preference for GA dinucleotides. This is the first occasion that an altered DNA sequence specificity has been demonstrated for a cisplatin analogue in human cells. A time course of DNA damage revealed that the DNA-targeted Pt complexes, consisting of four 9-Aminoacridine-4-carboxamide Pt complexes and one acridine-4-carboxamide Pt complex, damaged DNA more rapidly compared to cisplatin and non-targeted analogues. A comparison of the time taken to reach half the maximum relative intensity indicated that the DNA-targeted Pt complexes reacted approximately 4-fold faster than cisplatin and the non-targeted analogues.
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cis-Dichloroplatinum(II) complexes tethered to 9-Aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.
2001Co-Authors: Rodney J. Holmes, William A. Denny, Mark J. Mckeage, W. David McfadyenAbstract:A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-Aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-Aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-Aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-Aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-Aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-Aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.
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surface enhanced raman spectroscopic study of amsacrine and amsacrine dna interactions
1992Co-Authors: Thomas F Barton, Ralph P. Cooney, William A. DennyAbstract:Surface-enhanced Raman scattering (SERS) spectroscopy has been employed to study the interaction of intercalating ligands with DNA. SERS was used to obtain spectra of acridine, Aminoacridine, the 9-anilinoacridine amsacrine and related compounds at associated solution concentrations down to 1 μM. A major advantage of SERS was the near absence of fluorescence normally inherent in solution spectra of these compounds. SERS spectra of amsacrine–DNA complexes at various ligand/base pair ratios showed free ligand concentrations consistent with those calculated from the binding constant, and showed that the less strongly interacting acridine was largely unbound even at high ligand/base pair ratios.
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sequence specificity of the binding of 9 Aminoacridine and amsacrine 4 carboxamides to dna studied by dnase i footprinting
1992Co-Authors: Christian Bailly, William A. Denny, Laurence P. G. Wakelin, L E Mellor, Michael J WaringAbstract:: DNase I footprinting has been used to probe the sequence selectivity of binding of a series of intercalating amsacrine-4-carboxamides and a related 9-Aminoacridine-4-carboxamide to three DNA restriction fragments. These ligands have good experimental antileukemic activity, and for those members of the series that gave evaluable footprints, our principal finding is that they bind preferentially to GC-rich regions in agreement with the conclusion of equilibrium and kinetic measurements. The highest affinity sites generally occur in clusters of GC base pairs with runs of AT pairs being excluded from binding. It is important to appreciate that the 9-Aminoacridine- and amsacrine-4-carboxamides exhibit a very high degree of selectivity for GC sites which, to our knowledge, has not been previously matched by acridine derivatives in footprinting experiments. The principal determinant of specificity appears to be the 4-carboxamide group itself since neither variations in the terminal funtionality of the 4-carboxamide sidechain nor the presence of the 9-anilino substituent modifies sequence preferences. The molecular origins of selectivity may be discerned in terms of potential hydrogen bonding interactions between the 4-carboxamide moiety and carbonyl oxygen and amino groups of GC base pairs in the DNA minor groove at CG dinucleotide sites. The related therapeutic agent amsacrine failed to inhibit cleavage by DNase I, so no conclusion can be drawn concerning its binding selectivity, save to note that amsacrine does not possess the 4-carboxamide group which appears to be the crucial determinant of GC specificity. Whether selectivity for binding to GC-rich sequences is an important element in the antitumor activity of both the 9-Aminoacridine- and amsacrine-4-carboxamides remains to be determined.
Denis B. Tikhonov - One of the best experts on this subject based on the ideXlab platform.
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monoamine nmda receptor channel blockers inhibit and potentiate native and recombinant proton gated ion channels
2015Co-Authors: Tatiana B Tikhonova, Oleg I. Barygin, Elina I Nagaeva, Natalia N Potapieva, K V Bolshakov, Denis B. TikhonovAbstract:Acid-sensing ion channels (ASICs) are widely distributed in the peripheral and central nervous system. Although they are involved in many physiological functions, the actual processes that activate ASICs remain unclear. This is particularly true for brain ASICs, which produce only a transient response to a fast drop in pH and cannot mediate sustained current. Therefore, the search for ASIC inhibitors and, especially, potentiators/activators is important. We report that NMDA receptor channel blockers with a comparatively simple structure (9-Aminoacridine, memantine, IEM-2117 and IEM-1921) potentiate and/or inhibit ASICs in submillimolar concentrations. The experiments were performed using the patch clamp technique on native ASICs from rat hippocampal interneurons and recombinant ASICs of different subunit compositions expressed in CHO cells. Native ASICs were potentiated by IEM-1921 and IEM-2117, and inhibited by memantine and 9-Aminoacridine. Homomeric ASIC1a were inhibited by memantine, IEM-2117 and 9-Aminoacridine while IEM-1921 was ineffective. In contrast, homomeric ASIC2a were potentiated by IEM-2117, memantine and IEM-1921, whereas 9-Aminoacridine was inactive. The compounds caused a complex effect on ASIC3. 9-Aminoacridine and IEM-1921 potentiated the steady-state response of ASIC3 and inhibited the peak component. IEM-2117 not only potentiated ASIC3-mediated currents caused by acidification but also evoked steady-state currents at neutral pH. Our results demonstrate that, depending on the subunit composition, ASICs can be activated or inhibited by simple compounds that possess only amino group and aromatic/hydrophobic moieties. This opens up the possibility to search for new ASIC modulators among a number of endogenous ligands.
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9-Aminoacridine blocks NMDA and AMPA receptors by different mechanisms
2009Co-Authors: Oleg I. Barygin, V. E. Gmiro, Natalia V. Luchkina, Denis B. TikhonovAbstract:Tricyclic mono- and dicationic compounds (derivatives of 9-Aminoacridine) antagonize AMPA and NMDA glutamate receptors. The aim of the present study was to compare mechanisms of the 9-Aminoacridine action on AMPA and NMDA receptors. Experiments were carried out by whole-cell patch-clamp technique on native receptors from rat brain neurons. An important peculiarity of the 9-Aminoacridine action on NMDA receptors is the large slope of the concentration dependence, which suggests the binding of two molecules in the channel. AMPA receptors blockade also demonstrated interesting features. In contrast to the NMDA receptor channel block, inhibition of AMPA receptors is voltage-independent. 9-Aminoacridine and its dicationic analog demonstrated similar anti-AMPA activity. For classical AMPA-receptor channel blockers (derivatives of adamantane and phenylcyclohexyl) it was demonstrated that dicationic analogs are much more potent than monocationic analogs. We conclude that 9-Aminoacridine binds to a specific site in AMPA receptors. This finding opens a possibility to develop a new family of non-competitive antagonists of AMPA receptors.
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Blockade of NMDA receptor channels by 9-Aminoacridine and its derivatives.
2008Co-Authors: Oleg I. Barygin, V. E. Gmiro, Lev G. Magazanik, K. K. Kim, Denis B. TikhonovAbstract:9-Aminoacridine is known as "foot-in-the-door" NMDA receptor channel blocker because its binding prevents channel closure. Structural determinants of this mechanism of block were studied using a series of 9-Aminoacridine derivatives. Experiments were performed on native NMDA receptors of hippocampal pyramidal neurons, isolated from rat brain slices. The use-dependence of block and kinetics of recovery from block were used to characterize mechanism of block produced by the compounds. Modifications, which preserve the flat structure of the tricyclic 9-Aminoacridine moiety, affect blocking activity and kinetics but not the foot-in-the-door mechanism. On the contrary, disruption of the flat structure changes the mechanism of block to trapping. It is concluded that flat aromatic structure is one of the critical determinants of the action mechanism of 9-Aminoacridine.
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Mechanisms of blockade of glutamate receptor ionic channels: Paradox of 9-Aminoacridine
2007Co-Authors: K. H. Kim, V. E. Gmiro, Denis B. Tikhonov, Lev G. MagazanikAbstract:9-Aminoacridine and tacrine differ from other channel blockers of NMDA receptors in that their binding prevents the closing of blocked channels and subsequent dissociation of the agonist. Structural determinants of Aminoacridine derivatives underlying the blocking mechanism are still unknown. The aim of this study was to elucidate the effects of a dicationic 9-Aminoacridine derivative and some other tricyclic compounds on NMDA receptors of rat hippocampal pyramidal neurons. All the compounds under study are voltage-dependent blockers of NMDA channels; their IC50 values recorded at −80 mV vary from 1 to 50 µM. The dicationic derivatives demonstrate the same voltage dependence of the block as the monocationic derivatives. The monoand dicationic tricyclic compounds under study are weak blockers of AMPA receptor channels and differ from adamantane, phenylcyclohexyl and other dicationic derivatives that exhibit greater voltage dependence of the NMDA channel block and are able to induce effective suppression of AMPA channels. We conclude that the mechanisms of action of the tricyclic and dicationic 9-Aminoacridine derivatives are different from that of 9-Aminoacridine, since these compounds do not prevent closing of the blocked channels. This suggests that the binding site for 9-Aminoacridine has specific properties and high selectivity with respect to ligand structure.
Laurence P. G. Wakelin - One of the best experts on this subject based on the ideXlab platform.
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Homobivalent Conjugation Increases the Allosteric Effect of 9-Aminoacridine at the α1-Adrenergic Receptors
2016Co-Authors: Adrian P. Campbell, William A. Denny, Laurence P. G. Wakelin, Angela M. FinchAbstract:The α1-adrenergic receptors are targets for a number of cardiovascular and central nervous system conditions, but the current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1-adrenergic ligands, yet there is little information describing this drug class at the α1-adrenergic receptors. We have identified a series of 9-Aminoacridine compounds that demonstrate allosteric modulation of the α1A- and α1B-adrenergic receptors. The 9-Aminoacridines increase the rate of [3H]prazosin dissociation from the α1A- and α1B-adrenergic receptors and noncompetitively inhibit receptor activation by the endogenous agonist norepinephrine. The structurally similar compound, tacrine, which is a known allosteric modulator of the muscarinic receptors, is also shown to be a modulator of the α1-adrenergic receptors, which suggests a general lack of selectivity for allosteric binding sites across aminergic G protein-coupled receptor. Conjugation of two 9-Aminoacridine pharmacophores, using linkers of varying length, increases the potency and efficacy of the allosteric effects of this ligand, likely through optimization of bitopic engagement of the allosteric and orthosteric binding sites of the receptor. Such a bivalent approach may provide a mechanism for fine tuning the efficacy of allosteric compounds in future drug design efforts.
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dna threading bis 9 Aminoacridine 4 carboxamides effects of piperidine sidechains on dna binding cytotoxicity and cell cycle arrest
2008Co-Authors: Alexandra Eleftheriou, Malik Zihlif, Zhang Qing, Bernard W Stewart, Laurence P. G. WakelinAbstract:Abstract We describe the synthesis of a series of DNA-threading bis(9-Aminoacridine-4-carboxamides) comprising ethylpiperidino and N -methylpiperidin-4-yl sidechains, joined via neutral flexible alkyl chains, charged flexible polyamine chains and a semi-rigid charged piperazine linker. Their cytotoxicity towards human leukaemic cells gives IC 50 values ranging from 99 to 1100 nM, with the ethylpiperidino series generally being more cytotoxic than the N -methylpiperidin-4-yl series. Measurements with supercoiled DNA indicate that they bisintercalate.
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sequence specificity of the binding of 9 Aminoacridine and amsacrine 4 carboxamides to dna studied by dnase i footprinting
1992Co-Authors: Christian Bailly, William A. Denny, Laurence P. G. Wakelin, L E Mellor, Michael J WaringAbstract:: DNase I footprinting has been used to probe the sequence selectivity of binding of a series of intercalating amsacrine-4-carboxamides and a related 9-Aminoacridine-4-carboxamide to three DNA restriction fragments. These ligands have good experimental antileukemic activity, and for those members of the series that gave evaluable footprints, our principal finding is that they bind preferentially to GC-rich regions in agreement with the conclusion of equilibrium and kinetic measurements. The highest affinity sites generally occur in clusters of GC base pairs with runs of AT pairs being excluded from binding. It is important to appreciate that the 9-Aminoacridine- and amsacrine-4-carboxamides exhibit a very high degree of selectivity for GC sites which, to our knowledge, has not been previously matched by acridine derivatives in footprinting experiments. The principal determinant of specificity appears to be the 4-carboxamide group itself since neither variations in the terminal funtionality of the 4-carboxamide sidechain nor the presence of the 9-anilino substituent modifies sequence preferences. The molecular origins of selectivity may be discerned in terms of potential hydrogen bonding interactions between the 4-carboxamide moiety and carbonyl oxygen and amino groups of GC base pairs in the DNA minor groove at CG dinucleotide sites. The related therapeutic agent amsacrine failed to inhibit cleavage by DNase I, so no conclusion can be drawn concerning its binding selectivity, save to note that amsacrine does not possess the 4-carboxamide group which appears to be the crucial determinant of GC specificity. Whether selectivity for binding to GC-rich sequences is an important element in the antitumor activity of both the 9-Aminoacridine- and amsacrine-4-carboxamides remains to be determined.
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sequence specificity of the binding of 9 Aminoacridine and amsacrine 4 carboxamides to dna studied by dnase i footprinting
1992Co-Authors: Christian Bailly, William A. Denny, Laurence P. G. Wakelin, L E Mellor, Michael J WaringAbstract:DNase I footprinting has been used to probe the sequence selectivity of binding of a series of intercalating amsacrine-4-carboxamides and a related 9-Aminoacridine-4-carboxamide to three DNA restriction fragments. These ligands have good experimental antileukemic activity, and for those members of the series that gave evaluable footprints, our principal finding is that they bind preferentially to GC-rich regions in agreement with the conclusion of equilibrium and kinetic measurements. The highest affinity sites generally occur in clusters of GC base pairs with runs of AT pairs being excluded from binding
Clench - One of the best experts on this subject based on the ideXlab platform.
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Imaging Matrix Assisted Laser Desorption Ionization Mass Spectrometry: a technique to map plant metabolites within tissues at high spatial resolution
2006Co-Authors: Michael M. Burrell, Cj Earnshaw, ClenchAbstract:Imaging Matrix Assisted Laser Desorption Ionization Mass Spectrometry provides a new and powerful tool to analyse the distribution of metabolites within plant tissues. The two matrices alpha-cyano-4-hydroxycinnamic acid (alpha-CHCA) and 9-Aminoacridine provide a useful combination that allows the measurement of amino acids, sugars, and phosphorylated metabolites. Results are presented showing that representatives of these metabolites are unevenly distributed in wheat seeds at different stages of development and under temperature stress.
Vincent Murray - One of the best experts on this subject based on the ideXlab platform.
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characterising the atypical 5 cg dna sequence specificity of 9 Aminoacridine carboxamide pt complexes
2014Co-Authors: Hieronimus W. Kava, Anne M Galea, Farhana Md Jamil, Yue Feng, Vincent MurrayAbstract:In this study, the DNA sequence specificity of four DNA-targeted 9-Aminoacridine carboxamide Pt complexes was compared with cisplatin, using two specially constructed plasmid templates. One plasmid contained 5'-CG and 5'-GA insert sequences while the other plasmid contained a G-rich transferrin receptor gene promoter insert sequence. The damage profiles of each compound on the different DNA templates were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. With the plasmid that contained 5'-CG and 5'-GA dinucleotides, the four 9-Aminoacridine carboxamide Pt complexes produced distinctly different damage profiles as compared with cisplatin. These 9-Aminoacridine complexes had greatly increased levels of DNA damage at CG and GA dinucleotides as compared with cisplatin. It was shown that the presence of a CG or GA dinucleotide was sufficient to reveal the altered DNA sequence selectivity of the 9-Aminoacridine carboxamide Pt analogues. The DNA sequence specificity of the Pt complexes was also found to be similarly altered utilising the transferrin receptor DNA sequence.
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The sequence selectivity of DNA-targeted 9-Aminoacridine cisplatin analogues in a telomere-containing DNA sequence
2011Co-Authors: Moumita Paul, Vincent MurrayAbstract:In this study, the detailed DNA sequence specificity of four acridine Pt complexes was examined and compared with that of cisplatin. The DNA sequence specificity was determined in a telomere-containing DNA sequence using a polymerase stop assay, with a fluorescent primer and an automated capillary DNA sequencer. The Pt compounds included an acridine intercalating moiety that was modified to give a 9-Aminoacridine derivative, a 7-methoxy-9-Aminoacridine derivative, a 7-fluoro-9-Aminoacridine derivative and a 9-ethanolamine-acridine derivative. Compared with cisplatin, the DNA sequence specificity was most altered for the 7-methoxy-9-Aminoacridine compound, followed by the 9-Aminoacridine derivative, the 7-fluoro-9-Aminoacridine compound and the 9-ethanolamine-acridine derivative. The DNA sequence selectivity for the four acridine Pt complexes was shifted away from runs of consecutive guanines towards single guanine bases, especially 5′-GA dinucleotides and sequences that contained 5′-CG. The sequence specificity was examined in telomeric and non-telomeric DNA sequences. Although it was found that telomeric DNA sequences were extensively damaged by the four acridine Pt complexes, there was no extra preference for telomeric sequences.