text: Yohimbine dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype.
  Yohimbine is a potent and selective alpha2- versus alpha1-adrenoceptor antagonist. To date, drugs with high specificity for the alpha2-adrenoceptor show marginal selectivity among the three alpha2-adrenoceptor subtypes. Initial studies showed that yohimbine was about 4- and 15-fold more selective for the human alpha2C-adrenoceptor in comparison with the alpha2A- and alpha2B-adrenoceptors, respectively. To improve on this alpha2-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 alpha2-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for alpha2A- and alpha2C-adrenoceptor versus the alpha2B-adrenoceptor; and yohimbine dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the alpha2C-adrenoceptor. The yohimbine dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the alpha2C-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 alpha2C-adrenoceptor compared with the three alpha1-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 alpha2C-adrenoceptor.
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T2 T3 T4 T5 T6 T7 T8 T9
entities.type: GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y
entities.text: alpha2C-adrenoceptor alpha2-adrenoceptor alpha1-adrenoceptor alpha2C-adrenoceptor alpha2-adrenoceptor human alpha2C-adrenoceptor alpha2A- and alpha2B-adrenoceptors alpha2- versus alpha1-adrenoceptor alpha2-adrenoceptor human alpha2-adrenoceptor Yohimbine alpha2A- and alpha2C-adrenoceptor alpha2B-adrenoceptor alpha2C-adrenoceptor human alpha 2C-adrenoceptor cAMP yohimbine yohimbine yohimbine yohimbine yohimbine Yohimbine alpha2C-adrenoceptor