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.
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.
Vanover
Kimberly E
KE
ACADIA Pharmaceuticals, Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121-1402, USA. kvanover@acadia-pharm.com
Harvey
Scott C
SC
Son
Thomas
T
Bradley
Stefania Risso
SR
Kold
Henriette
H
Makhay
Malath
M
Veinbergs
Isaac
I
Spalding
Tracy A
TA
Weiner
David M
DM
Andersson
Carl Magnus
CM
Tolf
Bo-Ragnar
BR
Brann
Mark R
MR
Hacksell
Uli
U
Davis
Robert E
RE
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*
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