Ligand conformation has a definitive effect on 5-HT1A and serotonin reuptake affinity

Abstract Conformationally constrained aryl cyclohexanes and cyclohexenes based on aryl cyclohexanols 1 were prepared. Locking the aryl ring in plane with the cyclohexane moiety provided potent SSRIs 3 . Conversely, fixing the aryl ring perpendicular to the cyclohexane ring via a spiro lactone provided balanced 5-HT 1A antagonists with mid-nanomolar range SSRI potency (compounds 2 ).