CONFORMATIONAL FLEXIBILITY OF SEROTONIN(1A) RECEPTOR LIGANDS FROM CRYSTALLOGRAPHIC DATA - UPDATED MODEL OF THE RECEPTOR PHARMACOPHORE

Preparation and affinity to 5-HT1A and 5-HT2A receptors of new buspiro ne analogues 7-17 are reported. The compounds possess high to low affi nity to 5-HT1A and moderate to low to 5-HT2A receptors. The crystal st ructures have been determined for compounds 11, 12, 13, and 14. For lo w affinity ligand (15) of 5-HT1A receptor conformational analysis was performed and compared with similar analyses performed for know high ( buspirone 1) and very high (WY-48,723 2) affinity ligands of the recep tor. Structure-activity relationship is discussed for the affinity to 5-HT1A receptor. A three-point pharmocophore explaining interactions o f buspirone-like molecules with the receptor binding site is proposed.