Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands.

Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands. Research Abstract Details 

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Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands. Abstract Text:

Supriya A Bavadekar,Guoyi Ma,Suni M Mustafa,Bob M Moore,Duane D Miller,Dennis R Feller,

Yohimbine is a potent and relatively nonselective alpha(2)-adrenergic receptor (AR) antagonist. In an earlier report, we demonstrated that dimeric yohimbine analogs containing methylene and methylene-diglycine tethers were highly selective human alpha(2C)-AR ligands. Little work has been done to examine the role of the tether group or the absence of the second yohimbine pharmacophore on selectivity for human alpha(2)-AR subtypes. The goal of our study was to determine the binding affinities and functional subtype selectivities of a series of tethered yohimbine ligands in the absence of the second pharmacophore. The profiles of pharmacological activity for the yohimbine analogs on the three human alpha(2)-AR subtypes expressed in Chinese hamster ovary cells were examined using receptor binding and cAMP inhibition assays. All of the tethered yohimbine analogs exhibited higher binding affinities at the alpha(2C)- versus alpha(2A)- and alpha(2B)-AR subtypes. Notably, the benzyl carboxy alkyl amine and the carboxy alkyl amine analogs exhibited 43- and 1995-fold and 295- and 54-fold selectivities in binding to the alpha(2C)- versus alpha(2A)- and alpha(2B)-ARs, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities and selectivity profiles of selected compounds from the tethered series. The data demonstrate that the second pharmacophore may not be essential to obtain alpha(2C)-AR subtype selectivity, previously observed with the dimers. Further changes in the nature of the tether will help in optimization of the structure-activity relationship to obtain potent and selective alpha(2C)-AR ligands. These compounds may be used as pharmacological probes and in the treatment of human disorders.

Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands. Publishing Authors By Initials

SA Bavadekar,G Ma,SM Mustafa,BM Moore,DD Miller,DR Feller,

For similar heterocyclic compounds: alkaloids: indole alkaloids: secologanin tryptamine alkaloids: yohimbine research abstracts see: heterocyclic compounds: alkaloids: indole alkaloids: secologanin tryptamine alkaloids: yohimbine research

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Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: The Journal of pharmacology and experimental thera

VOLUME: 319

Page Numbers: 739-48

Journal Abbreviation: J. Pharmacol. Exp. Ther.

ISSN: 0022-3565

DAY: 27

MONTH: 07

YEAR: 2006

Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 376362

Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands. Keywords Mesh Terms:

KEYWORDS: Yohimbine

MESH TERMS: analogs & derivatives

Chemical & Substance for Abstract: Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands. Information

Substance Name: Medetomidine

Registry Number: 86347-14-0

Grant and Affiliation Information for Tethered yohimbine analogs as selective human alpha2C-adrenergic receptor ligands.

AFFILIATION: Department of Pharmacology and National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM 29358

ACRONYM: GM

MEDLINETA: J Pharmacol Exp Ther

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