Allosteric Inhibition and Pharmacochaperoning of the Serotonin Transporter by the Antidepressant Drugs Trazodone and Nefazodone.

Autor:	El-Kasaby A; Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology (A.E.-K., D.B., M.F., W.S.), Medical University of Vienna, Vienna, Austria; Department of Neurobiology, University of Vienna, Vienna, Austria (A.K., T.H.); and MRN Medical Research Network GmbH, Vienna, Austria (G.K.)., Boytsov D; Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology (A.E.-K., D.B., M.F., W.S.), Medical University of Vienna, Vienna, Austria; Department of Neurobiology, University of Vienna, Vienna, Austria (A.K., T.H.); and MRN Medical Research Network GmbH, Vienna, Austria (G.K.)., Kasture A; Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology (A.E.-K., D.B., M.F., W.S.), Medical University of Vienna, Vienna, Austria; Department of Neurobiology, University of Vienna, Vienna, Austria (A.K., T.H.); and MRN Medical Research Network GmbH, Vienna, Austria (G.K.)., Krumpl G; Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology (A.E.-K., D.B., M.F., W.S.), Medical University of Vienna, Vienna, Austria; Department of Neurobiology, University of Vienna, Vienna, Austria (A.K., T.H.); and MRN Medical Research Network GmbH, Vienna, Austria (G.K.)., Hummel T; Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology (A.E.-K., D.B., M.F., W.S.), Medical University of Vienna, Vienna, Austria; Department of Neurobiology, University of Vienna, Vienna, Austria (A.K., T.H.); and MRN Medical Research Network GmbH, Vienna, Austria (G.K.)., Freissmuth M; Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology (A.E.-K., D.B., M.F., W.S.), Medical University of Vienna, Vienna, Austria; Department of Neurobiology, University of Vienna, Vienna, Austria (A.K., T.H.); and MRN Medical Research Network GmbH, Vienna, Austria (G.K.)., Sandtner W; Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Centre of Physiology and Pharmacology (A.E.-K., D.B., M.F., W.S.), Medical University of Vienna, Vienna, Austria; Department of Neurobiology, University of Vienna, Vienna, Austria (A.K., T.H.); and MRN Medical Research Network GmbH, Vienna, Austria (G.K.).
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2024 Jun 18; Vol. 106 (1), pp. 56-70. Date of Electronic Publication: 2024 Jun 18.
DOI:	10.1124/molpharm.124.000881
Abstrakt:	The antidepressants trazodone and nefazodone were approved some 4 and 3 decades ago, respectively. Their action is thought to be mediated, at least in part, by inhibition of the serotonin transporter [SERT/solute carrier (SLC)-6A4]. Surprisingly, their mode of action on SERT has not been characterized. Here, we show that, similar to the chemically related drug vilazodone, trazodone and nefazodone are allosteric ligands: trazodone and nefazodone inhibit uptake by and transport-associated currents through SERT in a mixed-competitive and noncompetitive manner, respectively. Contrary to noribogaine and its congeners, all three compounds preferentially interact with the Na + -bound outward-facing state of SERT. Nevertheless, they act as pharmacochaperones and rescue the folding-deficient variant SERT-P601A/G602A. The vast majority of disease-associated point mutations of SLC6 family members impair folding of the encoded transporter proteins. Our findings indicate that their folding defect can be remedied by targeting allosteric sites on SLC6 transporters. SIGNIFICANCE STATEMENT: The serotonin transporter is a member of the solute carrier-6 family and is the target of numerous antidepressants. Trazodone and nefazodone have long been used as antidepressants. Here, this study shows that their inhibition of the serotonin transporter digressed from the competitive mode seen with other antidepressants. Trazodone and nefazodone rescued a folding-deficient variant of the serotonin transporter. This finding demonstrates that folding defects of mutated solute carrier-6 family members can also be corrected by allosteric ligands. (Copyright © 2024 by The Author(s).)
Databáze:	MEDLINE
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