AbstractThe pharmacological and binding properties of four β-adrenomimetic drugs with N-alkyl substitutions (isoprenaline, terbutaline, salbutamol and soterenol) were compared with those of four corresponding drugs with N-aralkyl substitutions (protokylol, ME 506, salmefamol and zinterol). BD-40 A, a very powerful β2-agonist with a related chemical structure, was also included in this study. The β1- and β2-activities of these drugs were determined on guinea-pig atria and trachea, their α-adrenolytic activity was measured on rat aorta and their affinities (Ki) for α1- and α2-adrenoceptors on rat cortical membranes were assessed using [3H]prazosin and [3H]yohimbine. In this group of β-agonists, substitution of the N-alkyl by an N-aralkyl group had a variable effect on the β2-selectivity whereas α-adrenolytic properties were always enhanced. An increase of the affinities (Ki) for both α1- and α2-adrenoceptors was found but the effect was much more pronounced for α1-adrenoceptors. These results indicated that the α-adrenolytic activity observed with the N-aralkyl β-agonists was selective for α1-adrenoceptors.

01 Oct 1979·Clinical ScienceQ2 · MEDICINE

The Adenylate Cyclase System in Human Liver: Characterization, Subcellular Distribution and Hormonal Sensitivity in Normal or Cirrhotic Adult, and in Foetal Liver

Q2 · MEDICINE

Article

Author: Berthelot, P. ; Hanoune, J. ; Pecker, F. ; Duvaldestin, P.

1. Adenylate cyclase (EC 4.6.1.1) activity was characterized in human liver, and its subcellular distribution compared with that of three other potential enzyme markers of the pericellular membrane: leucine aminopeptidase (EC 3.4.11.1), γ-glutamyltransferase (EC 2.3.2.2) and 5′-nucleotidase (EC 3.1.3.5). Although these three enzyme activities were detected in each of the subcellular fractions studied, 85% of the total adenylate cyclase activity was found in the 1000 g pellet (‘nuclear’ fraction) with a threefold increase in specific activity as compared with the homogenate. No adenylate cyclase activity existed in the 150 000 g supernatant fraction.2. In the ‘nuclear’ fraction, adenylate cyclase activity was increased in a dose-dependent fashion by glucagon with a half-maximal stimulation at 10 nmol/l and a maximal four- to seven-fold increase at 1 μmol/l. Catecholamines activated adenylate cyclase 2·5- to three-fold, with an order of potency (protokylol > isoprenaline > adrenaline > noradrenaline) typical of a β2-adrenoreceptor. Prostaglandin E1 and NaF also stimulated cyclase two- and four-fold respectively. Insulin, serotonin, dopamine, thyroid-stimulating hormone and ACTH had no effect. Adenosine provoked a weak inhibition at 0·1 mmol/l. Finally guanosine triphosphate and 5′-guanylyl imidodiphosphate induced a marked increase in basal activity, four- and eight-fold respectively, but both reduced the relative increase in enzyme activity due to glucagon or adrenaline.3. Cyclase from foetal liver (12–16 weeks old) and cirrhotic adult liver appeared to behave similarly to that from normal liver; however, foetal cyclase was more active, and cirrhotic enzyme less active than normal adult liver. Both systems responded to catecholamines via a β2-adrenoreceptor.4. These results validate the use of rat liver adenylate cyclase as a tool for pharmacological and physiological studies.

01 Aug 1979·European Journal of Biochemistry

Affinity Chromatography of the β‐Adrenergic Receptor from Turkey Erythrocytes

Article

Author: A. Donny Strosberg ; Philippe Geynet ; Georges Vauquelin ; Jacques Hanoune

The β1‐adrenergic receptors of turkey erythrocyte membranes have been identified by binding of the radioactively labeled antagonist (−)‐[3H]dihydroalprenolol, solubilized by treatment of the membranes with the detergent digitonin, and purified by affinity chromatography.Binding of (−)‐[3H]dihydroalprenolol to the membranes occurred to a single class of non‐cooperative binding sites (0.2–0.3 pmol/mg protein) with a equilibrium dissociation constant (Kd) of 8 (± 2) nM. These sites were identified as the functional, adenylate‐cyclase‐linked β1‐adrenergic receptors on the basis of: firstly, the fast association and dissociation binding kinetics at 30°C; secondly, the stereospecific displacement of bound (−)‐[3H]dihydroalprenolol by β‐adrenergic agonists and antagonists; and thirdly, the order of potencies for agonists to displace bound tracer (isoproterenol ≃ protokylol > norepinephrine ≃ epinephrine) similar to the one found for adenylate cyclase activation, and typical for β1‐adrenergic receptors. Treatment of the membranes with the detergent digitonin solubilized 30% of the receptors in an active form. Digitonin solubilized also adenylate cyclase activity with a yield of 20 to 30%, provided the membranes were first treated with an effector known to produce a persistent active state of the enzyme: e.g. sodium fluoride. Binding sites for guanine nucleotides ([3H]p[NH]ppG) were solubilized as well. Their concentration (24 pmol/mg protein) was in large excess over the concentration of solubilized receptors (0.30–0.45 pmol/mg protein). Solubilized receptors were purified 500–2000‐fold by affinity chromatography with a 25 to 35% yield, using an alprenolol‐agarose affinity matrix.Affinity purified receptors were devoid of measurable adenylate cyclase activity and guanine nucleotide binding sites, thus showing that receptors and adenylate cyclase are distinct membrane constituents, and that guanine nucleotides apparently do not bind directly to the receptor molecules.Membrane‐bound, solubilized and purified receptors were sensitive to inactivation by dithiothreitol, but not by N‐ethylmaleimide, suggesting that receptors are at least partly constituted of protein molecules, with essential disulfide bonds.

100 Deals associated with Protokylol Hydrochloride

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-	Protokylol Hydrochloride	-	DB06814

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