Vol. 303, Issue 3, 979-984, December 2002

Yohimbine Dimers Exhibiting Selectivity for the Human _2c-Adrenoceptor Subtype

Shilpa G. Lalchandani, Longping Lei, Weiping Zheng, Mustafa M. Suni, Bob M. Moore, Stephen B. Liggett, Duane D. Miller and Dennis R. Feller

Department of Pharmacology (S.G.L., L.L., D.R.F.) and National Center for Natural Products Research (D.R.F.), School of Pharmacy, University of Mississippi, University, Mississippi; Department of Pharmaceutical Sciences (W.Z., M.M.S., B.M.M., D.D.M.), College of Pharmacy, University of Tennessee-Memphis, Memphis, Tennessee; and Department of Medicine and Pharmacology (S.B.L.), College of Medicine, University of Cincinnati, Cincinnati, Ohio

Yohimbine is a potent and selective ₂- versus ₁-adrenoceptor antagonist. To date, drugs with high specificity for the ₂-adrenoceptor show marginal selectivity among the three ₂-adrenoceptor subtypes. Initial studies showed that yohimbine was about 4- and 15-fold more selective for the human _2C-adrenoceptor in comparison with the _2A- and _2B-adrenoceptors, respectively. To improve on this ₂-adrenoceptor subtype selectivity, a series of yohimbine dimers (varying from n = 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human ₂-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for _2A- and _2C-adrenoceptor versus the _2B-adrenoceptor; and yohimbine dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the _2C-adrenoceptor. The yohimbine dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the _2C-adrenoceptor in receptor binding and in functional studies (42- and 29-fold, respectively) measuring cAMP changes using a cell-based luciferase reporter gene assay. The dimers (n = 3 and n = 24) had high selectivity (>1000-fold) for the _2C-adrenoceptor compared with the three ₁-adrenoceptor subtypes. These findings demonstrate that the addition of spacer linkages to bivalent yohimbine molecules provides a successful approach to the development of ligands that are potent and highly selective for the _2C-adrenoceptor.