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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.
Vanover, Kimberly E; Harvey, Scott C; Son, Thomas; Bradley, Stefania Risso; Kold, Henriette; Makhay, Malath; Veinbergs, Isaac; Spalding, Tracy A; Weiner, David M; Andersson, Carl Magnus; Tolf, Bo-Ragnar; Brann, Mark R; Hacksell, Uli; Davis, Robert E.
Afiliación
  • Vanover KE; ACADIA Pharmaceuticals, Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121-1402, USA. kvanover@acadia-pharm.com
J Pharmacol Exp Ther ; 310(3): 943-51, 2004 Sep.
Article en En | MEDLINE | ID: mdl-15102927
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.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Antagonistas de la Serotonina / Benzamidas / Antagonistas del Receptor de Serotonina 5-HT2 Límite: Animals / Female / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2004 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Antagonistas de la Serotonina / Benzamidas / Antagonistas del Receptor de Serotonina 5-HT2 Límite: Animals / Female / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2004 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos