benzofurans and talopram

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.

Topics: Amino Acid Sequence; Animals; Antidepressive Agents; Base Sequence; Benzofurans; Binding Sites; Chlorocebus aethiops; Citalopram; COS Cells; Crystallization; DNA Mutational Analysis; Genetic Vectors; Humans; Models, Molecular; Molecular Sequence Data; Norepinephrine Plasma Membrane Transport Proteins; Propylamines; Radioligand Assay; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship

Citalopram and talopram are structurally closely related, but they have very distinct pharmacological profiles as selective inhibitors of the serotonin and norepinephrine transporters, respectively. A systematic structure-activity relationship study was performed, in which each of the four positions distinguishing the two compounds were varied. The inhibitory potencies of the resulting 16 compounds were tested at both serotonin and norepinephrine transporters. This showed that particularly two of the four positions are determinants for the biological activity.

Topics: Animals; Benzofurans; Blood Platelets; Brain; Cell Line; Citalopram; Humans; In Vitro Techniques; Norepinephrine Plasma Membrane Transport Proteins; Propylamines; Rats; Recombinant Proteins; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship; Synaptosomes

PET and SPECT ligands for the norepinephrine transporter (NET) will be important tools for studying the physiology, pathophysiology and pharmacology of the CNS noradrenergic system in vivo. A series of candidate NET ligands were synthesized and characterized in terms of their affinity for human monoamine transporters. The two most promising compounds, talopram and talsupram, were radiolabeled with carbon-11 and evaluated through biodistribution studies in rats and PET imaging studies in a rhesus monkey. Although both compounds displayed high affinity and selectivity for the human NET in vitro, these compounds did not enter the CNS in adequate amounts to be used in PET imaging studies.

Topics: Alkylation; Animals; Benzofurans; Binding, Competitive; Chromatography, High Pressure Liquid; Dopamine Plasma Membrane Transport Proteins; Indicators and Reagents; Ligands; Macaca mulatta; Male; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Norepinephrine Plasma Membrane Transport Proteins; Positron-Emission Tomography; Propylamines; Radiopharmaceuticals; Serotonin Plasma Membrane Transport Proteins; Spectrophotometry, Ultraviolet; Stereoisomerism; Symporters; Thiophenes; Tissue Distribution