Binding of spiperone analogs at 5-HT2A serotonin receptors

Although spiperone displays good selectivity for 5-HT2A versus 5-HT2C serot onin receptors, it suffers from high affinity for S-HT1A and dopamine D-2 r eceptors. In order to determine a) the contribution of various structural f eatures to 5-HT2A affinity, and b) if spiperone binds in a manner comparabl e to that of the 5-HT2 antagonist ketanserin, several abbreviated analogs o f spiperone were prepared and examined. Removal of the spiperone fluoro gro up enhances 5-HT2A affinity several-fold, but does not improve its selectiv ity. The butyrophenone carbonyl group is not a major contributor to binding , but removal of the triazaspirodecanone carbonyl group reduces affinity at all receptor populations by about 100-fold. For a series of spiperone anal ogs, a three- to four-atom chain seems optimal for 5-HT2A affinity. On the basis of the structure-activity findings, it is concluded that ketanserin a nd spiperone likely bind at 5-HT2A receptors in a dissimilar manner.