Abstract
Yohimbine is a potent and relatively nonselective α2-adrenergic receptor (AR) antagonist. In an earlier report, we demonstrated that dimeric yohimbine analogs containing methylene and methylene-diglycine tethers were highly selective human α2C-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 α2-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 α2-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 α2C- versus α2A- and α2B-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 α2C- versus α2A- and α2B-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 α2C-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 α2C-AR ligands. These compounds may be used as pharmacological probes and in the treatment of human disorders.
Footnotes
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This work was supported in part by U.S. Public Health Service Grant GM 29358 and U.S. Department of Agriculture ARS Agreement 58-6408-2-0009.
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The work was part of the doctoral dissertation of Supriya A. Bavadekar at the University of Mississippi, University, MS.
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The work has been previously presented, partially or entirely, at the following meetings: 1) Bavadekar SA, Ma G, Mustafa SM, Moore BM, Liggett SB, Miller DD, and Feller DR (2004) Tethered monomeric yohimbine analogs as selective human α2c-adrenergic receptor ligands, in Proceedings of the Southeastern Pharmacology Society Meeting; 2004 Nov 4–5; University, MI; 2) Mustafa SM, Bavadekar SA, Moore BM, Liggett SB, Feller DR, and Miller DD (2004) Synthesis and selectivity studies of yohimbine and its monomeric analogs on α2C-adrenergic receptors, in Proceedings of the 228th American Chemical Society National Meeting; 2004 Aug 22–26; Philadelphia; 3) Bavadekar SA, Suni MM, Moore BM, Liggett SB, Miller DD, and Feller DR (2004) Monomeric yohimbine analogs as selective human α2C-adrenergic receptor ligands, in Proceedings of Experimental Biology 2004; 2004 Apr 17–21; Washington DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.105981.
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ABBREVIATIONS: AR, adrenoceptor; CHO, Chinese hamster ovary; HEK, human embryonic kidney; CRE-LUC, cAMP response element-luciferase.
- Received April 10, 2006.
- Accepted July 20, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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