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NEUROPHARMACOLOGY

Pharmacological Characterization of AC-90179 [2-(4-Methoxyphenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide Hydrochloride]: A Selective Serotonin 2A Receptor Inverse Agonist

ACADIA Pharmaceuticals, Inc., San Diego, California

The primary purpose of the present series of experiments was to characterize the in vitro and in vivo pharmacology profile of 2-(4-methoxy-phenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride (AC-90179), a selective serotonin (5-HT_2A) receptor inverse agonist, in comparison with the antipsychotics haloperidol and clozapine. The secondary purpose was to characterize the pharmacokinetic profile of AC-90179. Like all atypical antipsychotics, AC-90179 shows high potency as an inverse agonist and competitive antagonist at 5HT_2A receptors. In addition, AC-90179 exhibits antagonism at 5HT_2C receptors. In contrast, AC-90179 does not have significant potency for D₂ and H₁ receptors that have been implicated in the dose-limiting side effects of other antipsychotic drugs. The ability of AC-90179 to block 5-HT_2A receptor signaling in vivo was demonstrated by its blockade of the rate-decreasing effects of the 5-HT_2A agonist, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride, under a fixed ratio schedule of reinforcement. Similar to clozapine and haloperidol, AC-90179 attenuated phencyclidine-induced hyperactivity. Although haloperidol impaired acquisition of a simple autoshaped response and induced cataleptic-like effects at behaviorally efficacious doses, AC-90179 and clozapine did not. Furthermore, unlike haloperidol and clozapine, AC-90179 did not decrease spontaneous locomotor behavior at efficacious doses. Limited oral bioavailability of AC-90179 likely reflects rapid metabolism rather than poor absorption. Taken together, a compound with a similar pharmacological profile as AC-90179 and with increased oral bioavailability may have potential for the treatment of psychosis.

Address correspondence to: Dr. Kimberly E. Vanover, ACADIA Pharmaceuticals, Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121-1402. E-mail: kvanover{at}acadia-pharm.com

This article has been cited by other articles:

				K. E. Vanover, D. M. Weiner, M. Makhay, I. Veinbergs, L. R. Gardell, J. Lameh, A. L. Del Tredici, F. Piu, H. H. Schiffer, T. R. Ott, et al. 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-Hydroxytryptamine2A Receptor Inverse Agonist J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 910 - 918. [Abstract] [Full Text] [PDF]