Synthesis, biological activity, and molecular modeling of selective 5-HT(2C/2B) receptor antagonists

Journal of Medicinal Chemistry
I T ForbesM D Wood

Abstract

The synthesis and biological activity are reported for a series of analogues of the previously published indole urea 2 (SB-206553), designed to probe the 5-HT(2C) receptor binding site. Small molecule modeling studies have been used to define a region in space which is allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor. In a complementary approach, docking of 2 into our model of the 5-HT(2C) receptor has allowed us to propose a novel primary binding interaction for this series of diaryl ureas, involving a potential double hydrogen-bonding interaction between the urea carbonyl oxygen of the ligand and two serine residues in the receptor. The difference of two valine residues in the 5-HT(2C) receptor for leucine residues in the 5-HT(2A) receptor is believed to account for the observed 5-HT(2C)/5-HT(2A) selectivity with 2.

Citations

Feb 9, 2011·Journal of Chemical Information and Modeling·Soo-Kyung KimWilliam A Goddard
Nov 25, 2003·Journal of Receptor and Signal Transduction Research·Caterina Bissantz
May 27, 2004·Developmental Dynamics : an Official Publication of the American Association of Anatomists·N BhasinJ M Lauder
Nov 15, 2013·Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række·Kristin M AakreHelle B Hager
Sep 15, 2005·Chemical Reviews·Francesca Fanelli, Pier G De Benedetti

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