RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 943
OP 951
DO 10.1124/jpet.104.066688
VO 310
IS 3
A1 Vanover, Kimberly E.
A1 Harvey, Scott C.
A1 Son, Thomas
A1 Bradley, Stefania Risso
A1 Kold, Henriette
A1 Makhay, Malath
A1 Veinbergs, Isaac
A1 Spalding, Tracy A.
A1 Weiner, David M.
A1 Andersson, Carl Magnus
A1 Tolf, Bo-Ragnar
A1 Brann, Mark R.
A1 Hacksell, Uli
A1 Davis, Robert E.
YR 2004
UL http://jpet.aspetjournals.org/content/310/3/943.abstract
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