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The discovery of a new series of compounds that are potent, selective 5-HT<inf>2C</inf> 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-HT<inf>2C</inf> receptor and excellent selectivity against the 5-HT<inf>2A</inf> and 5-HT<inf>2B</inf> 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 EC<inf>50</inf> of 4.2 nM at 5-HT<inf>2C</inf>, no activity at 5-HT<inf>2B</inf>, and an 89-fold selectivity against 5-HT<inf>2A</inf>, is one of the most potent and selective 5-HT<inf>2C</inf> agonists reported to date. The likely binding mode of this series of compounds to the 5-HT<inf>2C</inf> receptor was also investigated in a modeling study, using optimized models incorporating the structures of β<inf>2</inf>-adrenergic receptor and 5-HT<inf>2B</inf> receptor.
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]
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
2015
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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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/425072
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