Abstract

Yohimbine is a potent and selective α₂- versus α₁-adrenoceptor antagonist. To date, drugs with high specificity for the α₂-adrenoceptor show marginal selectivity among the three α₂-adrenoceptor subtypes. Initial studies showed that yohimbine was about 4- and 15-fold more selective for the human α_2C-adrenoceptor in comparison with the α_2A- and α_2B-adrenoceptors, respectively. To improve on this α₂-adrenoceptor subtype selectivity, a series of yohimbine dimers (varying fromn = 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human α₂-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for α_2A- and α_2C-adrenoceptor versus the α_2B-adrenoceptor; and yohimbine dimers with spacers ofn = 2, 3, 4, 18, and 24 exhibited selectivity for the α_2C-adrenoceptor. The yohimbine dimersn = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the α_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 α_2C–adrenoceptor compared with the three α₁-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 α_2C-adrenoceptor.