Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents
Articolo
Data di Pubblicazione:
2015
Citazione:
Optimization of 2-phenylcyclopropylmethylamines as selective serotonin 2C receptor agonists and their evaluation as potential antipsychotic agents / J. Cheng, P.M. Giguère, O.K. Onajole, W. Lv, A. Gaisin, H. Gunosewoyo, C.M. Schmerberg, V.M. Pogorelov, R.M. Rodriguiz, G. Vistoli, W.C. Wetsel, B.L. Roth, A.P. Kozikowski. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 58:4(2015 Feb 26), pp. 1992-2002. [10.1021/jm5019274]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
allyl compounds; amphetamine; animals; antipsychotic agents; CACO-2 cells; cytochrome P-450 enzyme system; dose-response relationship, drug; humans; locomotion; male; methylamines; mice; mice, inbred C57BL; microsomes, liver; models, molecular; molecular structure; receptor, serotonin, 5-HT2C; serotonin 5-HT2 receptor agonists; structure-activity relationship; molecular medicine; drug discovery3003 pharmaceutical science; medicine (all)
Elenco autori:
J. Cheng, P.M. Giguère, O.K. Onajole, W. Lv, A. Gaisin, H. Gunosewoyo, C.M. Schmerberg, V.M. Pogorelov, R.M. Rodriguiz, G. Vistoli, W.C. Wetsel, B.L. Roth, A.P. Kozikowski
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