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Research ArticleCELLULAR AND MOLECULAR

Yohimbine Dimers Exhibiting Selectivity for the Human α2c-Adrenoceptor Subtype

Shilpa G. Lalchandani, Longping Lei, Weiping Zheng, Mustafa M. Suni, Bob M. Moore, Stephen B. Liggett, Duane D. Miller and Dennis R. Feller
Journal of Pharmacology and Experimental Therapeutics December 2002, 303 (3) 979-984; DOI: https://doi.org/10.1124/jpet.102.039057
Shilpa G. Lalchandani
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Longping Lei
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Weiping Zheng
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Mustafa M. Suni
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Bob M. Moore
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Stephen B. Liggett
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Duane D. Miller
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Dennis R. Feller
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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 fromn = 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 ofn = 2, 3, 4, 18, and 24 exhibited selectivity for the α2C-adrenoceptor. The yohimbine dimersn = 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.

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Journal of Pharmacology and Experimental Therapeutics: 303 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 3
1 Dec 2002
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Research ArticleCELLULAR AND MOLECULAR

Yohimbine Dimers Exhibiting Selectivity for the Human α2c-Adrenoceptor Subtype

Shilpa G. Lalchandani, Longping Lei, Weiping Zheng, Mustafa M. Suni, Bob M. Moore, Stephen B. Liggett, Duane D. Miller and Dennis R. Feller
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 979-984; DOI: https://doi.org/10.1124/jpet.102.039057

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Research ArticleCELLULAR AND MOLECULAR

Yohimbine Dimers Exhibiting Selectivity for the Human α2c-Adrenoceptor Subtype

Shilpa G. Lalchandani, Longping Lei, Weiping Zheng, Mustafa M. Suni, Bob M. Moore, Stephen B. Liggett, Duane D. Miller and Dennis R. Feller
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 979-984; DOI: https://doi.org/10.1124/jpet.102.039057
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