RT Journal Article SR Electronic T1 Tethered Yohimbine Analogs as Selective Human α2C-Adrenergic Receptor Ligands JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 739 OP 748 DO 10.1124/jpet.106.105981 VO 319 IS 2 A1 Supriya A. Bavadekar A1 Guoyi Ma A1 Suni M. Mustafa A1 Bob M. Moore A1 Duane D. Miller A1 Dennis R. Feller YR 2006 UL http://jpet.aspetjournals.org/content/319/2/739.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics