Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding

Spiperone (1) is a widely used pharmacological tool that acts as a potent d opamine D-2, serotonin 5-HT1A, and serotonin 5-HT2A antagonist. Although sp iperone also binds at 5-HT2C receptors, it is one of the very few agents th at display some (ca. 1000-fold) binding selectivity for 5-HT2A versus 5-HT2 C receptors and, hence, might serve as a useful template for the developmen t of novel 5-HT2A antagonists if the impact of its various substituent grou ps 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 N-1-phenyl group with a methyl group only slightly decreased affini ty for cloned rat 5-HT2A receptors. However, N-1-methyl derivatives display ed significantly reduced affinity for 5-HT1A, 5-HT2C, and dopamine D-2 rece ptors. Several representative examples were shown to behave as 5-HT2 antago nists. As such, N-1-alkyl analogues of spiperone may afford entry into a no vel series of 5-HT2A-selective antagonists.