Characteristics of interaction of two derivatives of 2,2-diphenyl-2-ethylthioacetate with muscarinic receptors were studied in Chinese hamster ovary (CHO) cells stably transfected with the genes of human m2 and m3 muscarinic receptors. Data from radioligand-receptor binding assays and measurements of m2 receptor-inhibited cyclic AMP formation and m3 receptor-stimulated phosphoinositide (PI) hydrolysis showed that this new series of muscarinic receptor antagonists exhibited a middle range of affinities in binding to muscarinic receptors (Ki = 0.2-0.7 µmol/l), without being able to discriminate between m2 and m3 receptors. They completely displaced [3H]N-methylscopolamine ([3H]NMS) binding at equilibrium and inhibited receptor-mediated increase in PI turnover in m3 CHO cells and decrease in cyclic AMP synthesis in m2 CHO cells in an apparent competitive manner. However, higher concentrations of the compounds (>10 µmol/l) decelerated the kinetics of atropine-induced dissociation of [3H]NMS at m2 and m3 receptors, indicating an allosteric interaction. Collectively, our results demonstrate that these derivatives of 2,2-diphenyl-2-ethylthioacetate display a mixed mechanism of interaction with muscarinic receptors, being competitive at low concentrations and allosteric at higher concentrations. In contrast to previous reports of a significantly higher affinity at cardiac M2 as compared to ileal M3 receptor, these compounds do not exhibit such selectivity when the two receptor subtypes are expressed in the same type of cells.

Keywords:
Muscarinic receptor, Subtype selectivity, Allosteric interaction, Phosphoinositides, Cyclic AMP, Receptor binding
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© 1995 S. Karger AG, Basel
1995
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