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


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 ?2-adrenergic receptor and 5-HT2B receptor.

SUBMITTER: Cheng J 

PROVIDER: S-EPMC4834193 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Cheng Jianjun J   Giguère Patrick M PM   Onajole Oluseye K OK   Lv Wei W   Gaisin Arsen A   Gunosewoyo Hendra H   Schmerberg Claire M CM   Pogorelov Vladimir M VM   Rodriguiz Ramona M RM   Vistoli Giulio G   Wetsel William C WC   Roth Bryan L BL   Kozikowski Alan P AP  

Journal of medicinal chemistry 20150210 4


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-  ...[more]

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