Structure-activity relationship studies of citalopram derivatives: examining substituents conferring selectivity for the allosteric site in the serotonin transporter (original) (raw)

The serotonin transporter (SERT) is target for antidepressant drugs. SERT possesses two binding sites: the orthosteric (S1) binding site, which is the presumed target for current SERT inhibitors, and an allosteric (S2) site for which potential therapeutic effects are unknown. The antidepressant drug citalopram displays high-affinity S1 binding and low-affinity S2 binding. To elucidate a possible therapeutic role of allosteric inhibition of SERT a drug that specifically targets the allosteric site is required. The purpose of this study was to find a compound bearing higher selectivity towards the S2 site. We performed a systematic structure-activity relationship study based on the scaffold of citalopram and the structurally closely related congener, talopram, that shows low-affinity S1 binding in SERT. The role of the four chemical substituents, which distinguish citalopram from talopram in conferring selectivity towards the S1 and S2 site, respectively, was assessed by determining t...