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Inverse agonist activity of pirenzepine at M2 muscarinic acetylcholine receptors.

Fiche publication

Date publication

mars 1999

Journal

British journal of pharmacology

Auteurs

Membres identifiés du Cancéropôle Est :
Dr DAEFFLER Laurent


Tous les auteurs :
Daeffler L, Schmidlin F, Gies JP, Landry Y

Résumé

1. The intrinsic properties of muscarinic ligands were studied through their binding properties and their abilities to modulate the GTPase activity of G proteins coupled to muscarinic M2 receptors in pig atrial sarcolemma. 2. Competition binding experiments were performed with [3H]-oxotremorine-M to assess the affinity of receptors coupled to G proteins (R*), with [3H]-N-methylscopolamine ([3H]-NMS) to estimate the affinities of coupled and uncoupled receptors (R*+R) and with [3H]-NMS in the presence of GppNHp to assess the affinity of uncoupled receptors (R). 3. The ranking of Ki values for the agonist carbachol was R*R*+R>R (174, 155, 115 nM), suggesting inverse agonism. 4. The Vmax of the basal high affinity GTPase activity of pig atrial sarcolemma was increased by mastoparan and decreased by GPAnt-2 indicating the relevance of this activity to G proteins coupled to receptors (R*). The K(M) value (0.26-0.33 microM) was not modified by mastoparan or GPAnt-2. 5. Carbachol increased the Vmax of GTP hydrolysis (EC50 8.1+/-0.3 microM), whereas atropine and AF-DX 116, up to 1 mM, did not modify it. Pirenzepine decreased the Vmax of GTP hydrolysis (EC50 77.5+/-10.3 microM). This effect was enhanced when KCI was substituted for NaCl (EC50 11.0+/-0.8 microM) and was antagonized by atropine and AF-DX 116 (IC50 0.91+/-0.71 and 197+/-85 nM). 6. Pirenzepine is proposed as an inverse agonist and atropine and AF-DX 116 as neutral antagonists at the muscarinic M2 receptor.

Mots clés

Animals, GTP Phosphohydrolases, metabolism, GTP-Binding Proteins, metabolism, Muscarinic Antagonists, pharmacology, Peptides, Pirenzepine, pharmacology, Receptor, Muscarinic M2, Receptors, Muscarinic, drug effects, Sarcolemma, drug effects, Swine, Wasp Venoms, pharmacology

Référence

Br. J. Pharmacol.. 1999 Mar;126(5):1246-52