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    Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents

    Access Status
    Fulltext not available
    Authors
    Cheng, J.
    Giguère, P.
    Onajole, O.
    Lv, W.
    Gaisin, A.
    Gunosewoyo, Hendra
    Schmerberg, C.
    Pogorelov, V.
    Rodriguiz, R.
    Vistoli, G.
    Wetsel, W.
    Roth, B.
    Kozikowski, A.
    Date
    2015
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Cheng, J. and Giguère, P. and Onajole, O. and Lv, W. and Gaisin, A. and Gunosewoyo, H. and Schmerberg, C. et al. 2015. Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents. Journal of Medicinal Chemistry. 58 (4): pp. 1992-2002.
    Source Title
    Journal of Medicinal Chemistry
    DOI
    10.1021/jm5019274
    ISSN
    0022-2623
    School
    School of Pharmacy
    URI
    http://hdl.handle.net/20.500.11937/7396
    Collection
    • Curtin Research Publications
    Abstract

    The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.

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