Synthesis and biological studies of yohimbine derivatives on human α2C-adrenergic receptors

Mustafa, Suni M.; Bavadekar, Supriya A.; Ma, Guoyi; Moore, Bob M.; Feller, Dennis R.; Miller, Duane D.

doi:10.1016/j.bmcl.2005.03.116

Cited by 8 publications

(8 citation statements)

References 20 publications

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“…As described previously (Mustafa et al, 2005), the rank order of binding affinities exhibited by yohimbine (1) on the human ␣ 2 -AR subtypes was ␣ 2C Ն ␣ 2A Ͼ ␣ 2B , with 2-and 7-fold higher binding affinities for the ␣ 2C -versus the ␣ 2A -and ␣ 2B -ARs. Interestingly, studies with yohimbinic acid (2) revealed that this compound exhibited a greatly decreased binding potency at the ␣ 2A -AR (345-fold) versus the ␣ 2B -AR (2-fold) and the ␣ 2C -AR (20-fold), compared with yohimbine.…”

Section: Resultssupporting

confidence: 63%

“…Recently, Mustafa et al (2005) demonstrated that monomeric analogs of yohimbine, even in the absence of the second pharmacophore (or the second yohimbine molecule), with appendages or tethers of varying nature and composition retained high binding potencies, like that of the dimeric analogs, at the human ␣ 2C -AR. In fact, one of the tethered analogs, viz.…”

Section: Discussionmentioning

confidence: 99%

“…The main focus of our study was to determine whether the second pharmacophore was essential for the ␣ 2C -AR selectivity of the yohimbine dimers; i.e., would truncating dimeric analogs to tethered analogs still retain the ␣ 2C -AR selectivity? For this purpose, we have extended the evaluation of the tethered yohimbine analogs (Mustafa et al, 2005) to all human ␣ 2 -AR subtypes. The importance of the charge of the tethers, in potency and/or subtype selectivity, was investigated using neutral, basic, and acidic functional groups.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the exact mechanism underlying the ␣ 2C -AR selectivity observed for these dimeric compounds is unclear. An attempt to assess the role of the second pharmacophore and the spacer arm in the potency of dimeric ligands was recently made by Mustafa et al (2005). To achieve this, a monomeric tethered ligand versus a dimeric ligand approach was used.…”

mentioning

confidence: 99%

“…, TN). The procedures for synthesis of the tethered yohimbine analogs and the n ϭ 3 yohimbine dimer are as described by Mustafa et al (2005), Zheng et al (2000), and Zheng (1999). Solutions of the n ϭ 3 yohimbine dimer were prepared as described previously (Lalchandani et al, 2002).…”

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confidence: 99%

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Tethered Yohimbine Analogs as Selective Human α_2C-Adrenergic Receptor Ligands

Bavadekar¹,

Ma²,

Mustafa³

et al. 2006

J Pharmacol Exp Ther

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Yohimbine is a potent and relatively nonselective ␣ 2 -adrenergic receptor (AR) antagonist. In an earlier report, we demonstrated that dimeric yohimbine analogs containing methylene and methylene-diglycine tethers were highly selective human ␣ 2C -AR ligands. Little work has been done to examine the role of the tether group or the absence of the second yohimbine pharmacophore on selectivity for human ␣ 2 -AR subtypes. The goal of our study was to determine the binding affinities and functional subtype selectivities of a series of tethered yohimbine ligands in the absence of the second pharmacophore. The profiles of pharmacological activity for the yohimbine analogs on the three human ␣ 2 -AR subtypes expressed in Chinese hamster ovary cells were examined using receptor binding and cAMP inhibition assays. All of the tethered yohimbine analogs exhibited higher binding affinities at the ␣ 2C -versus ␣ 2A -and ␣ 2B -AR subtypes. Notably, the benzyl carboxy alkyl amine and the carboxy alkyl amine analogs exhibited 43-and 1995-fold and 295-and 54-fold selectivities in binding to the ␣ 2C -versus ␣ 2A -and ␣ 2B -ARs, respectively. Data from luciferase reporter gene assays confirmed the functional antagonist activities and selectivity profiles of selected compounds from the tethered series. The data demonstrate that the second pharmacophore may not be essential to obtain ␣ 2C -AR subtype selectivity, previously observed with the dimers. Further changes in the nature of the tether will help in optimization of the structureactivity relationship to obtain potent and selective ␣ 2C -AR ligands. These compounds may be used as pharmacological probes and in the treatment of human disorders.

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Section: Resultssupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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