title: Yohimbine dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Shilpa G
authors.initials: SG
authors.lastname: Lalchandani
authors.forename: Longping
authors.initials: L
authors.lastname: Lei
authors.forename: Weiping
authors.initials: W
authors.lastname: Zheng
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Suni
authors.forename: Bob M
authors.initials: BM
authors.lastname: Moore
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Feller
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000235:genetics / Q000494:pharmacology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D020218:Response Elements; D015016:Yohimbine / Q000031:analogs & derivatives* / Q000378:metabolism*
chemical_list: D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D000242:Cyclic AMP; D008156:Luciferases