Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters

Research output: Contribution to journalJournal articleResearchpeer-review

Jacob Andersen, Nicolai Stuhr-Hansen, Linda Zachariassen, Søren Toubro, Stinna Maria R Hansen, Jonas Nii Nortey Eildal, Andrew D Bond, Klaus P Bøgesø, Benny Bang-Andersen, Anders Skov Kristensen, Kristian Strømgaard

Inhibitors of the serotonin transporter (SERT) and norepinephrine transporter (NET) are widely used in the treatment of major depressive disorder. Although SERT/NET selectivity is a key determinant for the therapeutic properties of these drugs, the molecular determinants defining SERT/NET selectivity are poorly understood. In this study, the structural basis for selectivity of the SERT selective inhibitor citalopram and the structurally closely related NET selective inhibitor talopram is delineated. A systematic structure-activity relationship study allowed identification of the substituents that control activity and selectivity toward SERT and NET and revealed a common pattern showing that SERT and NET have opposite preference for the stereochemical configuration of these inhibitors. Mutational analysis of nonconserved SERT/NET residues within the central substrate binding site was performed to determine the molecular basis for inhibitor selectivity. Changing only five residues in NET to the complementary residues in SERT transferred a SERT-like affinity profile for R- and S-citalopram into NET, showing that the selectivity of these compounds is determined by amino acid differences in the central binding site of the transporters. In contrast, the activity of R- and S-talopram was largely unaffected by any mutations within the central substrate binding site of SERT and NET and in the outer vestibule of NET, suggesting that citalopram and talopram bind to distinct sites on SERT and NET. Together, these findings provide important insight into the molecular basis for SERT/NET selectivity of antidepressants, which can be used to guide rational development of unique transporter inhibitors with fine-tuned transporter selectivity.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number29
Pages (from-to)12137-12142
ISSN0027-8424
DOIs
Publication statusPublished - 19 Jul 2011

ID: 33811926