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

J Pharmacol Exp Ther. 2004 Sep;310(3):943-51. doi: 10.1124/jpet.104.066688. Epub 2004 Apr 21.

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.

MeSH terms

  • 3T3 Cells
  • Animals
  • Benzamides / adverse effects
  • Benzamides / blood
  • Benzamides / pharmacology*
  • Biological Availability
  • Brain / metabolism
  • Caco-2 Cells
  • Catalepsy / chemically induced
  • Cell Membrane Permeability / drug effects
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / drug effects
  • Motor Activity / drug effects
  • Nose / drug effects
  • Piperidines / adverse effects
  • Piperidines / blood
  • Piperidines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Serotonin 5-HT2 Receptor Antagonists*
  • Serotonin Antagonists / adverse effects
  • Serotonin Antagonists / blood
  • Serotonin Antagonists / pharmacology*

Substances

  • Benzamides
  • Piperidines
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide