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.
Lalchandani
Shilpa G
SG
Department of Pharmacology, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
Lei
Longping
L
Zheng
Weiping
W
Suni
Mustafa M
MM
Moore
Bob M
BM
Liggett
Stephen B
SB
Miller
Duane D
DD
Feller
Dennis R
DR
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*
D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D000242:Cyclic AMP; D008156:Luciferases