SYNTHESIS, BIOLOGICAL-ACTIVITY, AND MOLECULAR MODELING STUDIES OF SELECTIVE 5-HT2C 2B RECEPTOR ANTAGONISTS/

The synthesis and biological activity are reported for a series of ana logues of the previously published indole urea 2 (SB-206553), designed to probe the 5-HT2C receptor binding site. Small molecule modeling st udies have been used to define a region in space which is allowed at t he 5-HT2C receptor but disallowed at the 5-HT2A receptor. In a complem entary approach, docking of 2 into our model of the 5-HT2C receptor ha s allowed us to propose a novel primary binding interaction for this s eries of diaryl ureas, involving a potential double hydrogen-bonding i nteraction between the urea carbonyl oxygen of the ligand and two seri ne residues in the receptor. The difference of two valine residues in the 5-HT2C receptor for leucine residues in the 5-HT2A receptor is bel ieved to account for the observed 5-HT2C/5-HT2A selectivity with 2.