MolPharm

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


     

This Article
Right arrow Full Text (PDF)
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 Scherman, D.
Right arrow Articles by Henry, J. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scherman, D.
Right arrow Articles by Henry, J. P.

Hydrophobicity of the tetrabenazine-binding site of the chromaffin granule monoamine transporter

D Scherman, B Gasnier, P Jaudon and JP Henry

Institut de Biologie Physico-Chimique, Paris, France.

The catecholamine uptake inhibitor tetrabenazine (TBZ) binds to a high affinity site on the chromaffin granule membrane, presumably on the monoamine transporter. The hydrophobicity of the TBZ-binding site was investigated by comparing the potency of drugs to displace [3H]dihydrotetrabenazine (TBZOH), a ligand of the TBZ-binding site, with the lipophilicity of these drugs reflected by their octanol/buffer apparent partition coefficient (P o/b). Drugs tested were five substrates of the transporter, seven TBZ derivatives, and the inhibitors reserpine, haloperidol, and chlorpromazine. The validity of apparent P o/b as an index of lipophilicity was shown by measuring drug partitioning between buffer and chromaffin granule membranes. For most of the inhibitors tested, octanol/buffer and membrane/buffer apparent partition coefficients were correlated. For substrates of uptake and TBZ derivatives, the potency of a compound to displace [3H]TBZOH from its binding site was correlated to its apparent P o/b. This relationship was valid over a range of 5 orders of magnitude. These data are interpreted as indicating that the TBZ-binding site is hydrophobic and is in equilibrium with the ligand present in the membrane phase, and that substrates and TBZ derivatives are characterized by an equal intrinsic affinity for this site of about 1 microM. The 3-fold difference in affinity observed between alpha- and beta-diastereoisomers of TBZOH was accounted for by a similar difference in apparent P o/b. Reserpine, haloperidol, and chlorpromazine have much lower intrinsic affinity for the TBZ-binding site.

Volume 33, Issue 1, pp. 72-77, 01/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
M. K. Sievert and A. E. Ruoho
Peptide Mapping of the [125I]Iodoazidoketanserin and [125I]2-N-[(3'-Iodo-4'-azidophenyl)propionyl]tetrabenazine Binding Sites for the Synaptic Vesicle Monoamine Transporter
J. Biol. Chem., October 10, 1997; 272(41): 26049 - 26055.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. S. Thiriot and A. E. Ruoho
Mutagenesis and Derivatization of Human Vesicle Monoamine Transporter 2 (VMAT2) Cysteines Identifies Transporter Domains Involved in Tetrabenazine Binding and Substrate Transport
J. Biol. Chem., July 13, 2001; 276(29): 27304 - 27315.
[Abstract] [Full Text] [PDF]


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

Copyright © 1988 by the American Society for Pharmacology and Experimental Therapeutics