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TPA-023
TPA-023 is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a subtype-selective, mixed agonist-antagonist at GABAA receptors, which acts as a partial agonist at the α2 and α3 subtypes, but as a silent antagonist at α1 and α5 subtypes.〔Kohut SJ, Ator NA. Novel discriminative stimulus effects of TPA023B, subtype-selective gamma-aminobutyric-acid(A)/benzodiazepine modulator: comparisons with zolpidem, lorazepam, and TPA023. ''Pharmacology, Biochemistry and Behaviour''. 2008 Jul;90(1):65-73. PMID 18395780〕 It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50× the effective anxiolytic dose.〔Carling RW, Madin A, Guiblin A, Russell MG, Moore KW, Mitchinson A, Sohal B, Pike A, Cook SM, Ragan IC, McKernan RM, Quirk K, Ferris P, Marshall G, Thompson SA, Wafford KA, Dawson GR, Atack JR, Harrison T, Castro JL, Street LJ. 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models. J Med Chem. 2005 Nov 17;48(23):7089-92. PMID 16279764〕〔Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, Ragan I, Kerby J, Street L, Carling R, Castro JL, Whiting P, Dawson GR, McKernan RM. TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. ''Journal of Pharmacology and Experimental Therapeutics''. 2006 Jan;316(1):410-22. PMID 16183706〕
In human trials on healthy volunteers, TPA-023 was comparable to lorazepam, but had much less side effects on cognition, memory, alertness or coordination.〔de Haas SL, de Visser SJ, van der Post JP, de Smet M, Schoemaker RC, Rijnbeek B, Cohen AF, Vega JM, Agrawal NG, Goel TV, Simpson RC, Pearson LK, Li S, Hesney M, Murphy MG, van Gerven JM. Pharmacodynamic and pharmacokinetic effects of TPA023, a GABA(A) alpha(2,3) subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. ''Journal of Psychopharmacology''. 2007 Jun;21(4):374-83. PMID 17092968〕 In Phase II trials, the compound was significantly superior to placebo without inducing sedation. The clinical development was halted due to preclinical toxicity (cataract) in long term dosing studies.〔GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer. ''CNS Neuroscience and Therapeutics''. 2008 Spring;14(1):25-35. PMID 18482097〕 TPA-023 is well absorbed following oral administration and extensively metabolised by the liver, with a half-life of 6.7 hours.〔Polsky-Fisher SL, Vickers S, Cui D, Subramanian R, Arison BH, Agrawal NG, Goel TV, Vessey LK, Murphy MG, Lasseter KC, Simpson RC, Vega JM, Rodrigues AD. Metabolism and disposition of a potent and selective GABA-Aalpha2/3 receptor agonist in healthy male volunteers. ''Drug Metabolism and Disposition''. 2006 Jun;34(6):1004-11. PMID 16510541〕 The main enzyme involved in its metabolism is CYP3A4, with some contribution by CYP3A5.〔Ma B, Polsky-Fisher SL, Vickers S, Cui D, Rodrigues AD. Cytochrome P450 3A-dependent metabolism of a potent and selective gamma-aminobutyric acid A alpha2/3 receptor agonist in vitro: involvement of cytochrome P450 3A5 displaying biphasic kinetics. ''Drug Metabolism and Disposition''. 2007 Aug;35(8):1301-7. PMID 17460031〕
== References ==
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