Yohimbine dimers exhibiting selectivity for the human α2C-adrenoceptor subtype

Shilpa G. Lalchandani, Longping Lei, Weiping Zheng, Mustafa M. Suni, Bob Moore, Stephen B. Liggett, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

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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 α2C-adrenoceptor in comparison with the α2A- and α2B-adrenoceptors, respectively. To improve on this α2-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 α2-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for α2A- and α2C-adrenoceptor versus the α2B-adrenoceptor; and yohimbine dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the α2C-adrenoceptor. The yohimbine dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the α2C-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 α2C-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 α2C-adrenoceptor.

Original languageEnglish (US)
Pages (from-to)979-984
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume303
Issue number3
DOIs
StatePublished - Dec 1 2002

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Yohimbine
Adrenergic Receptors
Cricetulus
Luciferases
Reporter Genes
Ovary

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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Yohimbine dimers exhibiting selectivity for the human α2C-adrenoceptor subtype. / Lalchandani, Shilpa G.; Lei, Longping; Zheng, Weiping; Suni, Mustafa M.; Moore, Bob; Liggett, Stephen B.; Miller, Duane; Feller, Dennis R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 303, No. 3, 01.12.2002, p. 979-984.

Research output: Contribution to journalArticle

Lalchandani, Shilpa G. ; Lei, Longping ; Zheng, Weiping ; Suni, Mustafa M. ; Moore, Bob ; Liggett, Stephen B. ; Miller, Duane ; Feller, Dennis R. / Yohimbine dimers exhibiting selectivity for the human α2C-adrenoceptor subtype. In: Journal of Pharmacology and Experimental Therapeutics. 2002 ; Vol. 303, No. 3. pp. 979-984.
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