NOVEL AND SELECTIVE 5-HT2C 2B RECEPTOR ANTAGONISTS AS POTENTIAL ANXIOLYTIC AGENTS - SYNTHESIS, QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS, AND MOLECULAR MODELING OF SUBSTITUTED 1-(3-PYRIDYLCARBAMOYL)INDOLINES/

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. Th ese compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a rep lacement for fused five-membered rings in the context of 5-HT2C/2B rec eptor antagonists. By targeting a region of space previously identifie d as sterically allowed at the 5-HT2C receptor but disallowed at the 5 -HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported . 46 (SB-221284) was selected on the basis of its overall biological p rofile for further evaluation as a novel, potential nonsedating anxiol ytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.