Yohimbine dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype

J Pharmacol Exp Ther. 2002 Dec;303(3):979-84. doi: 10.1124/jpet.102.039057.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites / physiology
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cyclic AMP / genetics
  • Cyclic AMP / pharmacology
  • Dimerization
  • Dose-Response Relationship, Drug
  • Genes, Reporter
  • Humans
  • Luciferases / genetics
  • Radioligand Assay
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Response Elements
  • Yohimbine / analogs & derivatives*
  • Yohimbine / metabolism*


  • Receptors, Adrenergic, alpha-2
  • Yohimbine
  • Cyclic AMP
  • Luciferases