Synthesis, Biological Activity, and Molecular Modeling Studies of Selective 5-HT 2C/2B Receptor Antagonists
1996; American Chemical Society; Volume: 39; Issue: 25 Linguagem: Inglês
10.1021/jm960571v
ISSN1520-4804
AutoresIan T. Forbes, Steven Dabbs, D. Malcolm Duckworth, P. J. Ham, Graham E. Jones, Frank D. King, Damian V. Saunders, Frank E. Blaney, Christopher Naylor, Gordon S. Baxter, Thomas P. Blackburn, G.A. Kennett, Martyn Wood,
Tópico(s)Pharmacological Receptor Mechanisms and Effects
ResumoThe 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.
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