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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 2, 2007; DOI: 10.1124/jpet.107.125716

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*COCAINE
*CYCLOHEXANOL
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*VENLAFAXINE HYDROCHLORIDE


Received for publication May 22, 2007.
Revised August 1, 2007.
Accepted for publication August 1, 2007.

DESVENLAFAXINE SUCCINATE (DVS) IDENTIFIES NOVEL ANTAGONIST BINDING DETERMINANTS IN THE HUMAN NOREPINEPHRINE TRANSPORTER

John N. Mason 1, Darlene Coleman Deecher 2, Rhonda J. Richmond 1, Gary Stack 2, Paige E. Mahaney 2, Eugene Trybulski 2, Richard C. Winnaker 2, Randy D. Blakely 1*

1 Vanderbilt University School of Medicine 2 Wyeth Pharmaceuticals

* Address correspondence to: E-mail: randy.blakely{at}vanderbilt.edu

Abstract

Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine (NE) and serotonin (5HT) transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (Deecher et al., 2006) revealed significantly reduced potency for the hNET expressed in membranes as compared to whole cells when competing for [3H]nisoxetine (NIS) binding. Using hNET in transfected HEK-293 cells, this difference in potency for DVS at sites labeled by [3H]NIS was found to distinguish DVS, the DVS analog WY-46824, methylphenidate and the cocaine analog RTI-55 from other hNET antagonists such as NIS, mazindol, tricyclic antidepressants and cocaine. These differences appear not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular determinants that differentially define antagonist binding determinants, we identified Val148 in hNET transmembrane domain (TM) 3 where mutation selectively disrupts NIS binding but not that of DVS.


Key words: antidepressant, mutagenesis, norepinephrine, structure-function, transport, tricyclic


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