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Received for publication October 14, 2005.
Revised February 3, 2006.
Accepted for publication February 7, 2006.
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 [3H]-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.
Key words:
5-HT2A receptor, ACP-103, antipsychotic, behavioral pharmacology, inverse agonist, serotonin
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