PT  - JOURNAL ARTICLE
AU  - Vanover, Kimberly E.
AU  - Harvey, Scott C.
AU  - Son, Thomas
AU  - Bradley, Stefania Risso
AU  - Kold, Henriette
AU  - Makhay, Malath
AU  - Veinbergs, Isaac
AU  - Spalding, Tracy A.
AU  - Weiner, David M.
AU  - Andersson, Carl Magnus
AU  - Tolf, Bo-Ragnar
AU  - Brann, Mark R.
AU  - Hacksell, Uli
AU  - Davis, Robert E.
TI  - Pharmacological Characterization of AC-90179 [2-(4-Methoxyphenyl)-<em>N</em>-(4-methyl-benzyl)-<em>N</em>-(1-methyl-piperidin-4-yl)-acetamide Hydrochloride]: A Selective Serotonin 2A Receptor Inverse Agonist
AID  - 10.1124/jpet.104.066688
DP  - 2004 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 943--951
VI  - 310
IP  - 3
4099  - http://jpet.aspetjournals.org/content/310/3/943.short
4100  - http://jpet.aspetjournals.org/content/310/3/943.full
SO  - J Pharmacol Exp Ther2004 Sep 01; 310
AB  - 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-HT2A) 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 5HT2A receptors. In addition, AC-90179 exhibits antagonism at 5HT2C 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-HT2A receptor signaling in vivo was demonstrated by its blockade of the rate-decreasing effects of the 5-HT2A 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. The American Society for Pharmacology and Experimental Therapeutics