1-(1-phenethylpiperidin-4-yl)-1-phenylethanols 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 alpha1 and dopaminergic D2 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-fluorophenyl)-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=0.37 nM] and selectivity toward the dopaminergic D2- [IC50=2300 nM], adrenergic alpha1- [IC50=1000 nM] and 5-HT2C receptors [IC50=490 nM].