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 α1 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 α1‐ [IC50=1000 nM] and 5‐HT2C receptors [IC50=490 nM]. Mind your 'A's and 'C's: The R enantiomer of the tertiary alcohol (shown) is a highly potent antagonist of the serotonin receptor subtype 2A (5‐HT2A) and has greater than 1300‐fold selectivity for 5‐HT2A over the 2C receptor subtype, 5‐HT2C. The affinity and selectivity of this compound toward 5‐HT2A versus other relevant receptors (domaminergic D2 and adrenergic α1) was also optimized.