JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

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

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.107.125716v1
jpet.107.125716v2
jpet.107.125716v3
323/2/720    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mason, J. N.
Right arrow Articles by Blakely, R. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mason, J. N.
Right arrow Articles by Blakely, R. D.


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 L. 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


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
L. K. Henry and R. D. Blakely
Distinctions between Dopamine Transporter Antagonists Could be Just around the Bend
Mol. Pharmacol., March 1, 2008; 73(3): 616 - 618.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.