α1-adrenoceptors: Subtype- and organ-selectivity of different agents

Leonardi, Amedeo; Testa, Rodolfo; Motta, G; Benedetti, Pier G. De; Hieble, Paul; Giardinà, Dario

doi:10.1016/s0165-7208(96)80012-2

Cited by 20 publications

(19 citation statements)

References 45 publications

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“…The maximal dose of phenylephrine used increased the blood pressure above basal by 40 mmHg in the ␣ 1b ϩ͞ϩ, but only by 22 mmHg in the Ϫ͞Ϫ mice. The effect induced by 2 g͞kg of phenylephrine was almost completely inhibited in mice of both genotypes by the coadministration of two ␣ 1 -antagonists REC2739 and 3016 (22) administered intravenously at the dose of 10 g͞kg each 30 min before the agonist (results not shown). This supports the notion that the phenylephrine-induced response in vivo is mainly ␣ 1 -adrenergic.…”

Section: Resultsmentioning

confidence: 90%

Decreased blood pressure response in mice deficient of the α _1b -adrenergic receptor

Lattion

Hummler

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

276

222

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To investigate the functional role of different ␣ 1 -adrenergic receptor (␣ 1 -AR) subtypes in vivo, we have applied a gene targeting approach to create a mouse model lacking the ␣ 1b -AR (␣ 1b ؊͞؊). Reverse transcription-PCR and ligand binding studies were combined to elucidate the expression of the ␣ 1 -AR subtypes in various tissues of ␣ 1b ؉͞؉ and ؊͞؊ mice. Total ␣ 1 -AR sites were decreased by 98% in liver, 74% in heart, and 42% in cerebral cortex of the ␣ 1b ؊͞؊ as compared with ؉͞؉ mice. Because of the large decrease of ␣ 1 -AR in the heart and the loss of the ␣ 1b -AR mRNA in the aorta of the ␣ 1b ؊͞؊ mice, the in vivo blood pressure and in vitro aorta contractile responses to ␣ 1 -agonists were investigated in ␣ 1b ؉͞؉ and ؊͞؊ mice. Our findings provide strong evidence that the ␣ 1b -AR is a mediator of the blood pressure and the aorta contractile responses induced by ␣ 1 agonists. This was demonstrated by the finding that the mean arterial blood pressure response to phenylephrine was decreased by 45% in ␣ 1b ؊͞؊ as compared with ؉͞؉ mice. In addition, phenylephrine-induced contractions of aortic rings also were decreased by 25% in ␣ 1b ؊͞؊ mice. The ␣ 1b -AR knockout mouse model provides a potentially useful tool to elucidate the functional specificity of different ␣ 1 -AR subtypes, to better understand the effects of adrenergic drugs, and to investigate the multiple mechanisms involved in the control of blood pressure.

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Section: Resultsmentioning

confidence: 90%

Decreased blood pressure response in mice deficient of the α _1b -adrenergic receptor

Lattion

Hummler

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

276

222

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“…3), is an alkaloid extracted from the plant Fisostigma glaucescens, and its pharmacological profile has been assessed through some antagonism studies on NA‐induced contraction of rat aorta, spleen, and vas deferens 42. Although other classical α 1 antagonists (i.e., prazosin and terazosin) are more potent, we selected DSC also because of its α 1 ‐subtype selectivity profile (Ki α 1a = 617 nM; Ki α 1b = 363 nM; Ki α 1d = 25 nM)43 and its high affinity toward the α 1d receptor. Furthermore, DSC has a relatively low degree of conformational freedom (only four rotable bonds) and retains a certain structural similarity with NA.…”

Section: Resultsmentioning

confidence: 99%

Theoretical evidence of a salt bridge disruption as the initiating process for the α_1d‐adrenergic receptor activation: A molecular dynamics and docking study

et al. 2001

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This study reports the building of the three-dimensional structure of the rat alpha1d-adrenergic receptor through a topology approach based on the structure of the rhodopsin receptor from cryoelectron microscopy. The validity and reliability of the receptor model were assessed through exhaustive molecular dynamics and docking studies. Some interesting ligand-receptor interactions were identified along with significant differences between the binding mode of agonists and antagonists. The importance of the disruption of a salt bridge as a possible initial event leading to receptor activation is discussed on the basis of data from mutagenesis and molecular dynamics studies.

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“…Very few novel quinazolines for the treatment of BPH have emerged recently, although Recordati has claimed a series of piperazine- and piperidine-linked derivatives, e.g., 1 and 2 , that display few side effects as a result of increased selectivity for α 1b over α 1d mammalian cloned receptors (Table ) . In addition, (+)-cyclazosin (Table ), a prazosin derivative in which the piperazine linker is fused onto a cyclohexane ring, displays significant binding selectivity for α 1b …”

Section: α1 Adrenoceptor Structure−activitymentioning

confidence: 99%

Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia

et al. 1997

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α1-adrenoceptors: Subtype- and organ-selectivity of different agents

Cited by 20 publications

References 45 publications

Decreased blood pressure response in mice deficient of the α _1b -adrenergic receptor

Decreased blood pressure response in mice deficient of the α _1b -adrenergic receptor

Theoretical evidence of a salt bridge disruption as the initiating process for the α_1d‐adrenergic receptor activation: A molecular dynamics and docking study

Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia

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α1-adrenoceptors: Subtype- and organ-selectivity of different agents

Cited by 20 publications

References 45 publications

Decreased blood pressure response in mice deficient of the α 1b -adrenergic receptor

Decreased blood pressure response in mice deficient of the α 1b -adrenergic receptor

Theoretical evidence of a salt bridge disruption as the initiating process for the α1d‐adrenergic receptor activation: A molecular dynamics and docking study

Pharmacological Options in the Treatment of Benign Prostatic Hyperplasia

Contact Info

Product

Resources

About

Decreased blood pressure response in mice deficient of the α _1b -adrenergic receptor

Decreased blood pressure response in mice deficient of the α _1b -adrenergic receptor

Theoretical evidence of a salt bridge disruption as the initiating process for the α_1d‐adrenergic receptor activation: A molecular dynamics and docking study