Pharmacological Characterization of AC-90179: a Selective 5-HT 2A Receptor Inverse Agonist

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-HT 2A 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 5HT 2A receptors. In addition, AC-90179 exhibits antagonism at 5HT 2C receptors. In contrast, AC-90179 does not have significant potency for D 2 and H 1 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, 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. In vitro liver microsomes. AC-90179 was rapidly metabolized after incubation with mouse liver microsomes. With 59%, 34%, and 17% AC-90179 detected at 5, 10, and 20 min, respectively, after onset of incubation with an estimated half-life of 7 minutes and intrinsic clearance value of 94 µ l/min·mg.