1‐(1‐Phenethylpiperidin‐4‐yl)‐1‐phenylethanols as Potent and Highly Selective 5‐HT 2A Antagonists

The discovery of a novel class of highly potent and selective 5‐HT 2A antagonists is reported herein. Selectivity for the serotonin 5‐HT 2A receptor was optimized, decreasing the affinity of these antagonists toward the adrenergic α 1 and dopaminergic D 2 receptors, and especially to the 5‐HT 2C 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‐HT 2A receptor [IC 50 =0.37 n M ] and selectivity toward the dopaminergic D 2 ‐ [IC 50 =2300 n M ], adrenergic α 1 ‐ [IC 50 =1000 n M ] and 5‐HT 2C receptors [IC 50 =490 n M ].