Spiperone: Influence of spiro ring substituents on 5-HT(2A) serotonin receptor binding

Abstract

Spiperone (1) is a widely used pharmacological tool that acts as a potent dopamine D2, serotonin 5-HT(1A), and serotonin 5-HT(2A) antagonist. Although spiperone also binds at 5-HT(2C) receptors, it is one of the very few agents that display some (ca. 1000-fold) binding selectivity for 5- HT(2A) versus 5-HT(2C) receptors and, hence, might serve as a: useful template for the development of novel 5-HT(2A) antagonists if the impact of its various substituent groups on binding was known. In the present investigation we focused on the 1,3,8-triazaspiro[4.5]decanone portion of spiperone and found that replacement of the N1-phenyl group with a methyl group only slightly decreased affinity for cloned rat 5-HT(2A) receptors. However, N1-methyl derivatives displayed significantly reduced affinity for 5-HT(1A), 5-HT(2C), and dopamine D2 receptors. Several representative examples were shown to behave as 5-HT2 antagonists. As such, N1-alkyl analogues of spiperone may afford entry into a novel series of 5-HT(2A)- selective antagonists.