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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 317; no. 2; p. 910
• Main Authors: Vanover, Kimberly E, Weiner, David M, Makhay, Malath, Veinbergs, Isaac, Gardell, Luis R, Lameh, Jelveh, Del Tredici, Andria L, Piu, Fabrice, Schiffer, Hans H, Ott, Thomas R, Burstein, Ethan S, Uldam, Allan K, Thygesen, Mikkel B, Schlienger, Nathalie, Andersson, Carl Magnus, Son, Thomas Y, Harvey, Scott C, Powell, Susan B, Geyer, Mark A, Tolf, Bo-Ragner, Brann, Mark R, Davis, Robert E
• Format: Journal Article
• Language: English
• Published: United States 01-05-2006
• Subjects: Animals; Behavior, Animal - drug effects; Biological Availability; Cloning, Molecular; Humans; Male; Mice; NIH 3T3 Cells; Piperidines - pharmacokinetics; Piperidines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists - pharmacokinetics; Serotonin Antagonists - pharmacology; Urea - analogs & derivatives; Urea - pharmacokinetics; Urea - pharmacology
• ISSN: 0022-3565
• DOI: 10.1124/jpet.105.097006

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)-dihydroxybutanedioate (2:1) (ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonist ACP-103 competitively antagonized the binding of [(3)H]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 pIC(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 pIC(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 bioavailability 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.