title: 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-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.
authors.affiliation: ACADIA Pharmaceuticals, Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121-1402, USA. kvanover@acadia-pharm.com
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Vanover
authors.forename: Scott C
authors.initials: SC
authors.lastname: Harvey
authors.forename: Thomas
authors.initials: T
authors.lastname: Son
authors.forename: Stefania Risso
authors.initials: SR
authors.lastname: Bradley
authors.forename: Henriette
authors.initials: H
authors.lastname: Kold
authors.forename: Malath
authors.initials: M
authors.lastname: Makhay
authors.forename: Isaac
authors.initials: I
authors.lastname: Veinbergs
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Spalding
authors.forename: David M
authors.initials: DM
authors.lastname: Weiner
authors.forename: Carl Magnus
authors.initials: CM
authors.lastname: Andersson
authors.forename: Bo-Ragnar
authors.initials: BR
authors.lastname: Tolf
authors.forename: Mark R
authors.initials: MR
authors.lastname: Brann
authors.forename: Uli
authors.initials: U
authors.lastname: Hacksell
authors.forename: Robert E
authors.initials: RE
authors.lastname: Davis
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001549:Benzamides / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002375:Catalepsy / Q000139:chemically induced; D002463:Cell Membrane Permeability / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009666:Nose / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D010880:Piperidines; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; C492669:2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide