Investigating the effect of stereospecific fluorination on the potency and selectivity of the tricyclic antidepressant, imipramine

Imipramine is a tricyclic antidepressant (TCA) that inhibits the serotonin reuptake transporter (SERT). However, the clinical use of TCAs such as imipramine is limited by side-effects arising from antagonism of several off-target receptors. In this work, stereospecific fluorination is investigated as a strategy for enhancing the potency and selectivity of imipramine through conformational bias. In contrast to prediction, fluorination of imipramine is found to confer reduced potency and selectivity towards SERT, and this may be attributable to clashes between fluorine and hydroxyl‑bearing amino acid residues within the SERT binding site.