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Scott B Meikrantz - One of the best experts on this subject based on the ideXlab platform.
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comfa synthesis and pharmacological evaluation of e 3 2 carboxy 2 arylvinyl 4 6 dichloro 1h indole 2 carboxylic acids 3 2 3 aminophenyl 2 carboxyvinyl 4 6 dichloro 1h indole 2 carboxylic acid a potent selective glycine site NMDA Receptor Antagonist
Journal of Medicinal Chemistry, 2005Co-Authors: Bruce Baron, Robert J Cregge, Robert A Farr, Dirk Friedrich, Raymond S Gross, Boyd L Harrison, David A Janowick, Donald P Matthews, Timothy C Mccloskey, Scott B MeikrantzAbstract:(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective Antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) Receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA Receptor Antagonist.
Tomoki Nishiyama - One of the best experts on this subject based on the ideXlab platform.
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interaction between a NMDA Receptor Antagonist ap 5 and an ampa Receptor Antagonist ym 872 in antinociception in the spinal cord
Acta Anaesthesiologica Scandinavica, 2008Co-Authors: Tomoki NishiyamaAbstract:BACKGROUND: The intrathecal N-methyl-D-aspartate (NMDA) Receptor Antagonist, AP-5 and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) Receptor Antagonist, YM 872 showed inhibition on both acute and facilitated nociception in our previous study. The present study was performed to investigate the interaction between intrathecal AP-5 and YM 872 in antinociception for acute and chronic nociception. METHODS: Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of AP-5 or YM 872. The effects of the combination were tested by an isobolographic analysis using 50% effective dose (ED50). Total fractional dose was calculated as (ED50 dose of AP-5 in combination)/(ED50 dose of AP-5 alone)+(ED50 dose of YM 872 in combination)/(ED50 dose of YM 872 alone). RESULTS: Intrathecally administered AP-5, YM 872, and their combination produced dose-dependent increases of the tail-flick latency and decreases in the number of flinches in both phase 1 and 2 of the formalin test. The ED50 values of the combination were significantly lower than the calculated additive values (P<0.01). Total fractional dose value was 0.22 in the tail flick test, 0.12 in the phase 1 and 0.14 in the phase 2 of the formalin test. CONCLUSION: An NMDA Receptor Antagonist, AP-5 and an AMPA Receptor Antagonist, YM 872 had synergistic antinociceptive effects on both acute thermal and inflammatory induced acute and facilitated nociception.
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this article has been retracted interaction between a NMDA Receptor Antagonist ap 5 and an ampa Receptor Antagonist ym 872 in antinociception in the spinal cord
Acta Anaesthesiologica Scandinavica, 2008Co-Authors: Tomoki NishiyamaAbstract:Background: The intrathecal N-methyl-d-aspartate (NMDA) Receptor Antagonist, AP-5 and the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) Receptor Antagonist, YM 872 showed inhibition on both acute and facilitated nociception in our previous study. The present study was performed to investigate the interaction between intrathecal AP-5 and YM 872 in antinociception for acute and chronic nociception. Methods: Sprague–Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of AP-5 or YM 872. The effects of the combination were tested by an isobolographic analysis using 50% effective dose (ED50). Total fractional dose was calculated as (ED50 dose of AP-5 in combination)/(ED50 dose of AP-5 alone)+(ED50 dose of YM 872 in combination)/(ED50 dose of YM 872 alone). Results: Intrathecally administered AP-5, YM 872, and their combination produced dose-dependent increases of the tail-flick latency and decreases in the number of flinches in both phase 1 and 2 of the formalin test. The ED50 values of the combination were significantly lower than the calculated additive values (P<0.01). Total fractional dose value was 0.22 in the tail flick test, 0.12 in the phase 1 and 0.14 in the phase 2 of the formalin test. Conclusion: An NMDA Receptor Antagonist, AP-5 and an AMPA Receptor Antagonist, YM 872 had synergistic antinociceptive effects on both acute thermal and inflammatory induced acute and facilitated nociception.
Bruce Baron - One of the best experts on this subject based on the ideXlab platform.
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comfa synthesis and pharmacological evaluation of e 3 2 carboxy 2 arylvinyl 4 6 dichloro 1h indole 2 carboxylic acids 3 2 3 aminophenyl 2 carboxyvinyl 4 6 dichloro 1h indole 2 carboxylic acid a potent selective glycine site NMDA Receptor Antagonist
Journal of Medicinal Chemistry, 2005Co-Authors: Bruce Baron, Robert J Cregge, Robert A Farr, Dirk Friedrich, Raymond S Gross, Boyd L Harrison, David A Janowick, Donald P Matthews, Timothy C Mccloskey, Scott B MeikrantzAbstract:(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective Antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) Receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA Receptor Antagonist.
Daniel T Monaghan - One of the best experts on this subject based on the ideXlab platform.
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structure activity analysis of a novel nr2c nr2d preferring NMDA Receptor Antagonist 1 phenanthrene 2 carbonyl piperazine 2 3 dicarboxylic acid
British Journal of Pharmacology, 2004Co-Authors: Bihua Feng, Heong Wai Tse, Donald A Skifter, Richard M Morley, David E Jane, Daniel T MonaghanAbstract:(2S*,3R*)-1-(biphenyl-4-carbonyl)piperazine-2,3-dicarboxylic acid (PBPD) is a moderate affinity, competitive N-methyl-d-aspartate (NMDA) Receptor Antagonist with an atypical pattern of selectivity among NMDA Receptor 2 subunit (NR2) subunits. We now describe the activity of several derivatives of PBPD tested at both rat brain NMDA Receptors using l-[3H]-glutamate binding assays and at recombinant Receptors expressed in Xenopus oocytes. Substituting various branched ring structures for the biphenyl group of PBPD reduced NMDA Receptor activity. However, substituting linearly arranged ring structures - fluorenone or phenanthrene groups - retained or enhanced activity. Relative to PBPD, the phenanthrene derivative (2S*, 3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA) displayed a 30- to 78-fold increase in affinity for native NMDA Receptors. At recombinant Receptors, PPDA displayed a 16-fold (NR2B) to 94-fold (NR2C) increase in affinity over PBPD. Replacement of the biphenyl group of PBPD with a 9-oxofluorene ring system resulted in small changes in Receptor affinity and subtype selectivity. 2'-Bromo substitution on the biphenyl group of PBPD reduced Antagonist affinity 3- to 5-fold at NR2A-, NR2B- and NR2D-containing Receptors, but had little effect on NR2C-containing Receptors. In contrast, 4'-fluoro substitution of the biphenyl ring of PBPD selectively increased NR2A affinity. The aromatic rings of PBPD and PPDA increase Antagonist affinity and appear to interact with a region of the NMDA Receptor displaying subunit heterogeneity. PPDA is the most potent and selective NR2C/NR2D-preferring Antagonist yet reported and thus may be useful in defining NR2C/NR2D function and developing related Antagonists with improved NMDA Receptor subtype selectivity. British Journal of Pharmacology (2004) 141, 508-516. doi:10.1038/sj.bjp.0705644
Timothy C Mccloskey - One of the best experts on this subject based on the ideXlab platform.
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comfa synthesis and pharmacological evaluation of e 3 2 carboxy 2 arylvinyl 4 6 dichloro 1h indole 2 carboxylic acids 3 2 3 aminophenyl 2 carboxyvinyl 4 6 dichloro 1h indole 2 carboxylic acid a potent selective glycine site NMDA Receptor Antagonist
Journal of Medicinal Chemistry, 2005Co-Authors: Bruce Baron, Robert J Cregge, Robert A Farr, Dirk Friedrich, Raymond S Gross, Boyd L Harrison, David A Janowick, Donald P Matthews, Timothy C Mccloskey, Scott B MeikrantzAbstract:(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective Antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) Receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA Receptor Antagonist.