Pharmacological and Behavioral Profile of N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) Carbamide (2R,3R)-Dihydroxybutanedioate (2:1) (ACP-103),a Novel 5-Hydroxytryptamine_(2A) Receptor Inverse Agonist

摘要

The in vitro and in vivo pharmacological properties of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxy-butanedioate (2:1) (ACP-103) are presented.A potent 5-hydroxytryptamine (5-HT)_(2A) receptor inverse agonist ACP-103 competitively antagonized the binding of [~3H]ketanserin to heterologously expressed human 5-HT_(2A) receptors with a mean pK_i of 9.3 in membranes and 9.70 in whole cells.ACP-103 displayed potent,inverse agonist activity in the cell-based functional assay receptor selection- and amplification technology (R-SAT),with a mean plC_(50) of 8.7.ACP-103 demonstrated lesser affinity (mean pK_i of 8.80 in membranes and 8.00 in whole cells,as determined by radioligand binding) and potency as an inverse agonist (mean plC_(50) 7.1 in R-SAT) at human 5-HT_(2C) receptors,and lacked affinity and functional activity at 5-HT_(2B) receptors,dopamine D_2 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-HT_(2A) receptor agonist (+-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduced the hyperactivity induced in mice by the N-methyl-D-aspartate receptor noncompetitive antagonist 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate;MK-801) (0.1 and 0.3 mg/kg s.c.;3 mg/kg p.o.),consistent with a 5-HT_(2A) receptor mechanism of action in vivo and antipsychotic-like efficacy.ACP-103 demonstrated >42.6% oral bioavail-ability in rats.Thus,ACP-103 is a potent,efficacious,orally active 5-HT_(2A) receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent.