TPA-023

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TPA-023
TPA-023.png
Ball-and-stick model of the TPA-023 molecule
Clinical data
SynonymsMK-0777
Routes of
administration
oral
Pharmacokinetic data
Metabolismhepatic
Elimination half-life6.7 hours
Identifiers
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H22FN7O
Molar mass395.442 g·mol−1
3D model (JSmol)
  (verify)

TPA-023 (MK-0777) 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.[1] It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50 times the effective anxiolytic dose.[2][3]

In human trials on healthy volunteers, TPA-023 was comparable to lorazepam, but had much less side effects on cognition, memory, alertness or coordination.[4] 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.[5][6] TPA-023 is well absorbed following oral administration and extensively metabolised by the liver, with a half-life of 6.7 hours.[7] The main enzyme involved in its metabolism is CYP3A4, with some contribution by CYP3A5.[8]

References[edit]

  1. ^ Kohut, S. J.; Ator, N. A. (2008). "Novel discriminative stimulus effects of TPA023B, subtype-selective gamma-aminobutyric-acid(A)/Benzodiazepine modulator: Comparisons with zolpidem, lorazepam, and TPA023". Pharmacology, Biochemistry, and Behavior. 90 (1): 65–73. doi:10.1016/j.pbb.2008.02.019. PMC 3010402. PMID 18395780.
  2. ^ Carling, Robert W.; Madin, Andrew; Guiblin, Alec; Russell, Michael G. N.; Moore, Kevin W.; Mitchinson, Andrew; Sohal, Bindi; Pike, Andrew; Cook, Susan M.; Ragan, Ian C.; McKernan, Ruth M.; Quirk, Kathleen; Ferris, Pushpinder; Marshall, George; Thompson, Sally Ann; Wafford, Keith A.; Dawson, Gerard R.; Atack, John R.; Harrison, Timothy; Castro, José L.; Street, Leslie J. (2005). "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 γ-Aminobutyric AcidA(GABAA) α2/α3-Subtype Selective Agonist That Exhibits Potent Anxiolytic Activity but is Not Sedating in Animal Models". Journal of Medicinal Chemistry. 48 (23): 7089–7092. doi:10.1021/jm058034a. PMID 16279764.
  3. ^ Atack, J. R.; Wafford, K. A.; Tye, S. J.; Cook, S. M.; Sohal, B.; Pike, A.; Sur, C.; Melillo, D.; Bristow, L.; Bromidge, F.; Ragan, I.; Kerby, J.; Street, L.; Carling, R.; Castro, J. L.; Whiting, P.; Dawson, G. R.; McKernan, R. M. (2006). "TPA023 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo4,3-bpyridazine, an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates". The Journal of Pharmacology and Experimental Therapeutics. 316 (1): 410–22. doi:10.1124/jpet.105.089920. PMID 16183706.
  4. ^ De Haas, S. L.; De Visser, S. J.; Van Der Post, J. P.; De Smet, M.; Schoemaker, R. C.; Rijnbeek, B.; Cohen, A. F.; Vega, J. M.; Agrawal, N. G.; Goel, T. V.; Simpson, R. C.; Pearson, L. K.; Li, S.; Hesney, M.; Murphy, M. G.; Van Gerven, J. M. (2007). "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 (Oxford, England). 21 (4): 374–83. doi:10.1177/0269881106072343. PMID 17092968.
  5. ^ Möhler, Hanns (June 2011). "The rise of a new GABA pharmacology". Neuropharmacology. 60 (7–8): 1042–1049. doi:10.1016/j.neuropharm.2010.10.020. PMID 21035473.
  6. ^ Atack, J. R. (2008). "GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/Alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer". CNS Neuroscience & Therapeutics. 14 (1): 25–35. doi:10.1111/j.1527-3458.2007.00034.x. PMID 18482097.
  7. ^ Polsky-Fisher, S. L.; Vickers, S.; Cui, D.; Subramanian, R.; Arison, B. H.; Agrawal, N. G.; Goel, T. V.; Vessey, L. K.; Murphy, M. G.; Lasseter, K. C.; Simpson, R. C.; Vega, J. M.; Rodrigues, A. D. (2006). "Metabolism and disposition of a potent and selective GABA-Aalpha2/3 receptor agonist in healthy male volunteers". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 34 (6): 1004–11. doi:10.1124/dmd.105.008193. PMID 16510541.
  8. ^ Ma, B.; Polsky-Fisher, S. L.; Vickers, S.; Cui, D.; Rodrigues, A. D. (2007). "Cytochrome P450 3A-dependent metabolism of a potent and selective gamma-aminobutyric acid Aalpha2/3 receptor agonist in vitro: Involvement of cytochrome P450 3A5 displaying biphasic kinetics". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 35 (8): 1301–7. doi:10.1124/dmd.107.014753. PMID 17460031.