High affinity non-β-adrenoceptor binding of β-adrenergic ligands

Rademaker, B.; Krämer, K.; Stroes, Jan W.; Vlug, Jan; Krielaart, M. J.; Zaagsma, Johan

doi:10.1016/0014-2999(85)90110-4

Cited by 27 publications

(10 citation statements)

References 7 publications

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“…Our own analysis of log P and pK values for 11 ligands tested in rat skeletal muscle, shows a correlation which is not stronger for the 'atypical' binding site than for binding to classical 132-adrenoceptors (unpublished data). Furthermore, the pK value for phentolamine observed in the present study (3.64) is not consistent with that reported in Cheng liver cells, so we conclude that the 'atypical' rat and bovine ['251]-ICYP binding sites are not the same as the non-3-adrenoceptor site described by Rademaker et al (1985). As well as binding to lipophilic sites, ['251]-ICYP has been shown to label 5-HT receptors (Hoyer et al, 1985) and to be susceptible to tissue peroxidases, which cause the nonspecific incorporation of iodide free radicles into tyrosine residues of membrane proteins (Rigby et al, 1988).…”

Section: Resultscontrasting

confidence: 99%

“…Rademaker et al (1985) identified such a site in Cheng liver cells, by observing a strong correlation between binding affinity and hydrophobicity for 10 ligands, and a high affinity for the lipophilic x-adrenoceptor antagonist, phentolamine (pK 5.5), relative to that of the hydrophilic 13-agonist isoprenaline. Our own analysis of log P and pK values for 11 ligands tested in rat skeletal muscle, shows a correlation which is not stronger for the 'atypical' binding site than for binding to classical 132-adrenoceptors (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Classical and atypical binding sites for β‐adrenoceptor ligands and activation of adenylyl cyclase in bovine skeletal muscle and adipose tissue membranes

Sillence

Matthews

1994

British J Pharmacology

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Section: Resultscontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Classical and atypical binding sites for β‐adrenoceptor ligands and activation of adenylyl cyclase in bovine skeletal muscle and adipose tissue membranes

Sillence

Matthews

1994

British J Pharmacology

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“…In the following study, the receptor-binding technique was used to determine the affinity and selectivity of racemic SPFF and its isomers for b 1 -and b 2 -adrenoceptor, using (Ϫ)[ 125 I]pindolol as radioligand, because it has various characteristics, such as its stereoisomeric purity, its very high specific radioactivity and affinity and its lack of a hydrophobic hydroxybenzyl group, 21) which make (Ϫ)[ 125 I]pindolol an excellent choice for use in radioligand binding assays. The result showed that (Ϫ)-SPFF's binding affinity was about 6 and 164 times greater than that of (Ϯ)-and (ϩ)-SPFF in the lung membrane, which may predominantly account for its more potent efficacy in experiments in vitro.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Enantiomers of SPFF, a Novel .BETA.2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs

Hao

Zhang

et al. 2008

Biological & Pharmaceutical Bulletin

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b 2 -Adrenoceptor agonists, the most effective bronchodilator, have long been widely used in symptomatic therapy of asthma. A variety of b 2 -adrenoceptor agonists are currently available, such as salbutamol, terbutaline, salmeterol, formoterol and procaterol. The majority of b 2 -adrenoceptor agonists possess chiral center(s) (asymmetric carbon atom) in their structures; therefore, they exist as pair(s) of enantiomers.1) Based on the conformational stereochemistry and pharmacokinetic parameters, enantiomers can vary greatly in their pharmacological effects on target tissue(s).2) Except for levalbuterol, most available b 2 -adrenoceptor agonists are a racemic mixture of equimolar (R)-and (S)-enantiomer. Against this background, separation of enantiomers is a practice increasing in popularity, since a single optical isomer may represent a safer and more efficacious alternative than its corresponding racemate.3) 2-(4-Amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride (SPFF) is synthesized and exploited by the drug synthesis laboratory of Shenyang Pharmaceutical University as a novel b 2 -adrenoceptor agonist. Gan et al. 4) has found that bronchodilator effects of racemic SPFF on isolated guinea pig trachea strips with or without precontraction of bronchoconstrictors (histamine and acetylcholine) were more potent than isoprenaline. Moreover, it was confirmed that the bronchodilator effect of racemic SPFF was due to the activation of b 2 -adrenoceptor because this effect was easily antagonized by a specific b 2 -adrenoceptor antagonist, ICI-118551 (pA 2 ϭ8.90Ϯ0.01). Furthermore, the positive chronotropic effect of SPFF on isolatd guinea pig left atria (pD 2 ϭ5.41Ϯ0.38) was much weaker than that of isoprenaline (pD 2 ϭ8.75Ϯ0.24). A radioligand binding experiment using guinea pig lung and cardiac ventricle as b 2 and b 1 adrenoceptor sources, respectively, also demonstrated that racemic SPFF possesses high affinity and selectivity to b 2 -adrenoceptor. The protective effect of racemic SPFF on bronchospasm induced by bronchoconstrictor aerosol in guinea pig in vivo was 6 times more potent than that of sulbutamol, and the Konzett and Rösler experiment performed in anesthetized rabbits showed that racemic SPFF exerted action of longer duration than sulbutamol did. In the present study we compared the pharmacological effects of racemic SPFF with its individual enantiomers on bronchodilating action and potency in guinea pigs. MATERIALS AND METHODS Chemicals and Drugs

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“…The somewhat lower affinity of 12sI-ICYP to receptors on intact cells, compared to results in the particulate preparation, may be due to the high fraction of non-specific binding, which makes determination of specific binding uncertain, and possibly some interference from the non-specific binding component. The inclusion of phentolamine or lysosomotropic amines in radioligand binding studies is a commonly used procedure to reduce non-specific binding (Dulis & Wilson 1981;Mews et al 1982;Rademaker et al 1985;Fabisiak et al 1986).…”

Section: Discussionmentioning

confidence: 99%

“…In the present study we have extended our observations to intact hepatocytes because these are closer to the in vivo situation, and to exclude the possibility of variable receptor loss during the preparative procedure. The identification of P-adrenoceptors on intact cells is often complicated by a high fraction of non-specific binding of radioligand (Dulis & Wilson 1981;Meier & Ruoho 1984;Rademaker et al 1985;Fabisiak et al 1986). The introduction of the hydrophilic radioligand 'H-CGP-12177 has facilitated binding studies in intact cells, due to its low grade of nonspecific binding (Staehelin et al 1983).…”

mentioning

confidence: 99%

Elevated Level of β‐Adrenoceptors in Intact Hepatocytes from Partially Hepatectomized Rats

Sandnes¹,

Sager²,

Sand³

et al. 1988

Pharmacology & Toxicology

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The binding characteristics of 125I-iodocyanopindolol (125I-ICYP) and 3H-CGP-12177 to intact hepatocytes and a particulate fraction prepared from hepatocytes from sham-operated and partially hepatectomized rats were compared. In the particulate fraction, the beta-adrenoceptor number increased 4-10-fold after partial hepatectomy. 125I-ICYP binding to intact cells demonstrated a high fraction of non-specific binding, although phentolamine was included in the assay to reduce non-specific binding. 3H-CGP-12177 binding to intact cells also demonstrated a higher fraction of non-specific binding than in most cell types. In intact cells, the beta-adrenoceptor number increased 5-6-fold after partial hepatectomy. The number of receptors was comparable in intact cells and the broken cell preparation, indicating that receptors are conserved during the preparation of the particulate fraction.

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High affinity non-β-adrenoceptor binding of β-adrenergic ligands

Cited by 27 publications

References 7 publications

Classical and atypical binding sites for β‐adrenoceptor ligands and activation of adenylyl cyclase in bovine skeletal muscle and adipose tissue membranes

Classical and atypical binding sites for β‐adrenoceptor ligands and activation of adenylyl cyclase in bovine skeletal muscle and adipose tissue membranes

Comparison of Enantiomers of SPFF, a Novel .BETA.2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs

Elevated Level of β‐Adrenoceptors in Intact Hepatocytes from Partially Hepatectomized Rats

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