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Research ArticleNEUROPHARMACOLOGY

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

Kimberly E. Vanover, Scott C. Harvey, Thomas Son, Stefania Risso Bradley, Henriette Kold, Malath Makhay, Isaac Veinbergs, Tracy A. Spalding, David M. Weiner, Carl Magnus Andersson, Bo-Ragnar Tolf, Mark R. Brann, Uli Hacksell and Robert E. Davis
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 943-951; DOI: https://doi.org/10.1124/jpet.104.066688
Kimberly E. Vanover
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Scott C. Harvey
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Thomas Son
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Stefania Risso Bradley
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Henriette Kold
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Malath Makhay
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Isaac Veinbergs
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Tracy A. Spalding
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David M. Weiner
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Carl Magnus Andersson
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Bo-Ragnar Tolf
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Mark R. Brann
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Uli Hacksell
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Robert E. Davis
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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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.104.066688.

  • ABBREVIATIONS: D, dopamine; 5-HT, serotonin; H, histamine; AC-90179, 2-(4-methoxy-phenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide hydrochloride; DOI, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride; R-SAT, receptor selection and amplification technology; DMEM, Dulbecco's modified Eagle's medium; FR, fixed ratio; LC, liquid chromatography; MS, mass spectrometry; KBB, Krebs bicarbonate buffer; DMSO, dimethyl sulfoxide.

    • Received February 9, 2004.
    • Accepted April 15, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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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
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Research ArticleNEUROPHARMACOLOGY

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

Kimberly E. Vanover, Scott C. Harvey, Thomas Son, Stefania Risso Bradley, Henriette Kold, Malath Makhay, Isaac Veinbergs, Tracy A. Spalding, David M. Weiner, Carl Magnus Andersson, Bo-Ragnar Tolf, Mark R. Brann, Uli Hacksell and Robert E. Davis
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 943-951; DOI: https://doi.org/10.1124/jpet.104.066688

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Research ArticleNEUROPHARMACOLOGY

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

Kimberly E. Vanover, Scott C. Harvey, Thomas Son, Stefania Risso Bradley, Henriette Kold, Malath Makhay, Isaac Veinbergs, Tracy A. Spalding, David M. Weiner, Carl Magnus Andersson, Bo-Ragnar Tolf, Mark R. Brann, Uli Hacksell and Robert E. Davis
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 943-951; DOI: https://doi.org/10.1124/jpet.104.066688
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