>>J Pharmacol Exp Ther. 2004 Apr 21 [Epub ahead of print]
Pharmacological Characterization of AC-90179: a Selective 5-HT2A Receptor Inverse Agonist.
Vanover KE, Harvey SC, Son T, Risso Bradley S, Kold H, Makhay M, Veinbergs I, Spalding TA, Weiner DM, Andersson CM, Tolf BR, Brann MR, Hacksell U, Davis RE.
ACADIA Pharmaceuticals.
The primary purpose of the present series of experiments was to characterize the in vitro and in vivo pharmacology profile of AC-90179, a selective 5-HT2A receptor inverse agonist, in comparison to 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, DOI, under a fixed ratio schedule of reinforcement. Similar to clozapine and haloperidol, AC-90179 attenuated phencyclidine-induced hyperactivity. Whereas haloperidol impaired acquisition of a simple autoshaped response and induced cataleptic-like effects at behaviorally efficacious doses, AC-90179 and clozapine did not. Further, 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.<<
Rapid metabolism . . . maybe an extended release version would help? Don't know enough pharmacology to know what the standard tweaks are for that problem.
Cheers, Tuck |
