1-(1-phenethylpiperidin-4-yl)-1-phenylethanois as potent and highly selective 5-HT2A antagonists

The discovery of a novel class of highly potent and selective 5-HT2A antagonists is reported herein. Selectivity for the serotonin 5-HT2A receptor was optimized, decreasing the affinity of these antagonists toward the adrenergic alpha(1) and dopaminergic D-2 receptors, and especially to the 5-HT2C receptor. A series of corresponding 7-substituted indoles is described for the first time as serotonergic ligands. The enantiomer R-(+)-1-(4-fluoropheny1)-1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl} ethanol (R-(+)-74) was identified to have superior affinity for the serotonergic 5-HT2A receptor [IC50=0.37nm] and selectivity toward the dopaminergic D-2- [IC50=2300 nm], adrenergic alpha(1)- [IC50 = 1000 nm] and 5-HT2C receptors [IC50 = 490 nm].