Simplified analogues of ritanserin and their affinity at 5-HT2A, 5-HT2B and 5-HT2C serotonin receptors

The 5-HT2 serotonin antagonist ritanserin (6-{2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl}-7-methyl-5H-thiazole[3,2-a]pyrimidin-5-one, 2) binds with high affinity to 5-HT2A, 5-HT2B and 5-HT2C serotonin receptors. With the aim of exploring how simplification of the thiazolepyrimidinone nucleus of 2 affects the affinity and selectivity for 5-HT2A, 5-HT2B and 5-HT2C subtypes, some derivatives of 4-[bis(4-fluorophenyl)methylene]piperidine were synthesized, and their 5-HT2A and 5-HT2C receptor binding affinities and 5-HT2B antagonistic affinity evaluated. The new compounds bind the three 5-HT2 subtypes with lower affinity than did 2. Simplification of the thiazolepyrimidinone nucleus of ritanserin has only slight influence on the selectivity for 5-HT2 subtypes. The results suggest that the thiazolepyrimidinone moiety participates in key binding interactions and is determinant for high affinity at 5-HT2 receptor subtypes. Some derivatives showed antagonistic activity at 5-HT2A receptor. (C) Elsevier, Paris.