[Pharmacological and behavioral profile of ACP-103, a novel 5-HT2A receptor inverse agonist]
>>J Pharmacol Exp Ther. 2006 Feb 9; [Epub ahead of print]
Pharmacological and behavioral profile of ACP-103, a novel 5-HT2A receptor inverse agonist.
Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE.
ACADIA Pharmaceuticals.
The in vitro and in vivo pharmacological properties of ACP-103 [N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1)] are presented. A potent 5-HT2A receptor inverse agonist, ACP-103 competitively antagonized the binding of [(3)H]-ketanserin to heterologously expressed human 5-HT2A receptors with a mean pKi of 9.3 in membranes and 9.70 in whole cells. ACP-103 displayed potent inverse agonist activity in the cell-based functional assay R-SAT, with a mean pIC50 of 8.7. ACP-103 demonstrated lesser affinity (mean pKi 8.80, membranes, and 8.00, whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC50 7.1 in R-SAT) at human 5-HT2C receptors, and lacked affinity and functional activity at 5-HT2B receptors, dopamine D2 receptors, and other human monoaminergic receptors. Behaviorally, ACP-103 attenuated head twitch behavior (3 mg/kg, p.o.) and prepulse inhibition deficits (1 - 10 mg/kg, s.c.) induced by the 5-HT2A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in rats and reduced the hyperactivity induced in mice by the N-methyl-D-aspartate receptor non-competitive antagonist, MK-801, (0.1 and 0.3 mg/kg, s.c.; 3 mg/kg, p.o.) consistent with a 5-HT2A receptor mechanism of action in vivo and antipsychotic-like efficacy. ACP-103 demonstrated > 42.6% oral bioavailability in rats. Thus, ACP-103 is a potent, efficacious, orally active, 5-HT2A receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent.<<
Cheers, Tuck |
