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

Abstract

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 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, (Ϯ)-2,5-dimethoxy-4-iodoamphetamine hydrochloride, under a fixed ratio schedule of reinforcement. Similar to clozapine and haloperidol, AC-90179 attenuated phencyclidineinduced 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 5-HT2A Receptor (5-HT2AR) Regulates Impulsive Action and Cocaine Cue Reactivity in Male Sprague-Dawley Rats

“…Pimavanserin is marketed as a 5-HT 2A R inverse agonist to treat Parkinson disease psychosis (Vanover et al, 2008;Meltzer et al, 2010;Sahli and Tarazi, 2018). Both pimavanserin and M100907 act as 5-HT 2A R inverse agonists to attenuate basal constitutive 5-HT 2A R signaling in cells designed with overexpression of the native 5-HT 2A R or transfection with a 5-HT 2A R mutation targeted to increase constitutive activity (Weiner et al, 2001;Vanover et al, 2004;Muntasir et al, 2006;Vanover et al, 2006). A definitive role for negative 5-HT 2A R efficacy in the control of behavior is suggested by a limited literature in conditioned behaviors (Welsh et al, 1998;Romano et al, 2006).…”

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

“…In contrast, clozapine substantially decreased locomotion below levels of vehicle-treated animals when administered alone or in combination with DOI, mirroring its sedative effects in humans, a side effect that may translate to the oftreported "empty-headed" sensation caused by available antipsychotic drugs (Moritz et al, 2013). It is noteworthy that a recent paper reports that the hypolocomotion effect of clozapine, which is a 5-HT 2A receptor inverse agonist of the canonical 5-HT 2 -G q signaling pathway (Vanover et al, 2004), is mediated by 5-HT 2A receptors (Williams et al, 2012). The affinity of clozapine and (2)-MBP at rodent 5-HT 2A receptors is very similar, suggesting that the inverse-agonist effects of clozapine and neutral-antagonist effects of (2)-MBP at 5-HT 2A receptors may translate to different behavioral outcomes or that the compounds are functionally selective regarding 5-HT 2A signaling that affects locomotion.…”

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

“…Of the initial 500 hits, 100 were characterized as potent 5-HT 2A inverse agonists. Following further screening for selectivity and subsequent lead optimization, AC-90179 was identified as a selective 5-HT 2A inverse agonist [26]. It had nearly 100 fold selectivity for 5-HT 2A receptors compared to 5-HT 2B , 5-HT 2C and 5-HT 6 receptors as an inverse agonist.…”