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Online ISSN: 1860-7187
June 15, 2010
VIP: HTS and Rational Drug Design to Generate a Class of 5-HT2C-Selective Ligands for Possible Use in Schizophrenia
Alan P. Kozikowski,* Sung Jin Cho, Niels H. Jensen, John A. Allen, Andreas M. Svennebring, and Bryan L. Roth
The 5-HT2C receptor is distributed widely in the central nervous system (CNS), and 5-HT2C agonists have shown efficacy in preclinical models of depression, obesity, addiction, and psychosis. Targeting 5-HT2C would be a promising way to address CNS disorders; however, 5-HT2C is homologous to the two other receptor family members, 5-HT2A and 5-HT2B, and so it is crucial that 5-HT2C agonists have minimal or no activity toward these subtypes.
In an effort to improve specificity, Kozikowski et al. carried out stepwise structural modifications to existing 5-HT2C agonists, and identified a series of compounds with marked improvements: potency toward 5-HT2C on par with reference compounds, but with much greater specificity, and an improved pharmacokinetic profile.
Received April 30, 2010; published online June 10, 2010, DOI: 10.1002/cmdc.201000186.