DEVELOPMENT OF A RECEPTOR-INTERACTION MODEL FOR SEROTONIN 5-HT2 RECEPTOR ANTAGONISTS - PREDICTING SELECTIVITY WITH RESPECT TO DOPAMINE D-2 RECEPTORS

A receptor-interaction model for serotonin 5-HT2 receptor antagonists has been developed by conformational analysis with molecular mechanics (MM2(91)) and superimposition studies of serotonin 5-HT2 receptor ant agonists. Substituted 3-(4-piperidinyl)-, 1-(4-piperidinyl)-, 3-(1,2,3 ,6-tetrahydropyridin-4-yl)-, and 1-(1,2,3,6-tetrahydropyridin-4-yl)-1H -indoles, substituted 3-(4-fluorophenyl)-1-(4-piperazinyl)indans, cypr oheptadine derivatives, ritanserin, and danitracene have been used as bases for the model. Other serotonin 5-HT2 receptor antagonists, such as ketanserin and MDL 11,939, are well accommodated into the model. Co mparison of the model with a recently described receptor-interaction m odel for dopamine D-2 receptor antagonists suggests a common pharmacop hore for dopamine D-2 and serotonin 5-HT2 receptor antagonists. Import ant steric differences between 5-HT2 receptor antagonists with additio nal high affinity for dopamine D-2 receptors and serotonin 5-HT2 recep tor antagonists with high selectivity versus D-2 receptors are describ ed. The geometry of the receptor-interaction model described is signif icantly different from that of a recently reported receptor-interactio n model for 5-HT2 receptor agonists and antagonists developed by use o f (+)-LSD as a template, suggesting the existence of two binding modes at the 5-HT2 receptor.