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Research ArticleNEUROPHARMACOLOGY

5-Hydroxytryptamine2A Receptor Inverse Agonists as Antipsychotics

D. M. Weiner, E. S. Burstein, N. Nash, G. E. Croston, E. A. Currier, K. E. Vanover, S. C. Harvey, E. Donohue, H. C. Hansen, C. M. Andersson, T. A. Spalding, D. F. C. Gibson, K. Krebs-Thomson, S. B. Powell, M. A. Geyer, U. Hacksell and M. R. Brann
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 268-276;
D. M. Weiner
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E. S. Burstein
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N. Nash
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G. E. Croston
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E. A. Currier
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K. E. Vanover
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S. C. Harvey
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E. Donohue
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H. C. Hansen
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C. M. Andersson
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T. A. Spalding
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D. F. C. Gibson
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K. Krebs-Thomson
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S. B. Powell
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M. A. Geyer
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Abstract

We have used a cell-based functional assay to define the pharmacological profiles of a wide range of central nervous system active compounds as agonists, competitive antagonists, and inverse agonists at almost all known monoaminergic G-protein-coupled receptor (GPCR) subtypes. Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are potent competitive antagonists of the dopamine D2 receptor. Surprisingly, this analysis also revealed that most are potent and fully efficacious 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. No other molecular property was shared as universally by this class of compounds. Furthermore, comparisons of receptor potencies revealed that antipsychotics with the highest extrapyramidal side effects (EPS) liability are significantly more potent at D2 receptors, the EPS-sparing atypical agents had relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors. Functional high-throughput screening of a diverse chemical library identified 530 ligands with inverse agonist activity at 5-HT2A receptors, including several series of compounds related to known antipsychotics, as well as a number of novel chemistries. An analog of one of the novel chemical series, AC-90179, was pharmacologically profiled against the remaining monoaminergic GPCRs and found to be a highly selective 5-HT2A receptor inverse agonist. The behavioral pharmacology of AC-90179 is characteristic of an atypical antipsychotic agent.

Footnotes

  • ↵1 D.M.W. was supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award.

  • ↵2 Current address: Dow Pharmaceutical Sciences, 1330A Redwood Way, Petaluma, CA 94954.

  • This work was supported in part by National Institute on Drug Abuse Grant DA02925.

  • Abbreviations:
    GPCR
    G-protein coupled receptor
    5-HT
    5-hydroxytryptamine
    DMSO
    dimethyl sulfoxide
    m5CAM
    m5 constitutively activated mutant
    R-SAT
    Receptor Selection and Amplification
    DMEM
    Dulbecco's modified essential media
    PSG
    penicillin/streptomycin/glutamine
    DOI
    (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride
    ANOVA
    analysis of variance
    PPI
    prepulse inhibition
    • Received April 16, 2001.
    • Accepted June 16, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleNEUROPHARMACOLOGY

5-Hydroxytryptamine2A Receptor Inverse Agonists as Antipsychotics

D. M. Weiner, E. S. Burstein, N. Nash, G. E. Croston, E. A. Currier, K. E. Vanover, S. C. Harvey, E. Donohue, H. C. Hansen, C. M. Andersson, T. A. Spalding, D. F. C. Gibson, K. Krebs-Thomson, S. B. Powell, M. A. Geyer, U. Hacksell and M. R. Brann
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 268-276;

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Research ArticleNEUROPHARMACOLOGY

5-Hydroxytryptamine2A Receptor Inverse Agonists as Antipsychotics

D. M. Weiner, E. S. Burstein, N. Nash, G. E. Croston, E. A. Currier, K. E. Vanover, S. C. Harvey, E. Donohue, H. C. Hansen, C. M. Andersson, T. A. Spalding, D. F. C. Gibson, K. Krebs-Thomson, S. B. Powell, M. A. Geyer, U. Hacksell and M. R. Brann
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 268-276;
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