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Propiverine and metabolites: differences in binding to muscarinic receptors and in functional models of detrusor contraction

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Abstract

Propiverine is a commonly used antimuscarinic drug used as therapy for symptoms of an overactive bladder. Propiverine is extensively biotransformed into several metabolites that could contribute to its spasmolytic action. In fact, three propiverine metabolites (M-5, M-6 and M-14) have been shown to affect various detrusor functions, including contractile responses and L-type calcium-currents, in humans, pigs and mice, albeit with different potency. The aim of our study was to provide experimental evidence for the relationship between the binding of propiverine and its metabolites to human muscarinic receptor subtypes (hM1–hM5) expressed in chinese hamster ovary cells, and to examine the effects of these compounds on muscarinic receptor-mediated detrusor function. Propiverine, M-5, M-6 and M-14 bound to hM1–hM5 receptors with the same order of affinity for all five subtypes: M-6 > propiverine > M-14 > M-5. In HEK-293 cells expressing hM3, carbachol-induced release of intracellular Ca2+ ([Ca2+]i) was suppressed by propiverine and its metabolites; the respective concentration-response curves for carbachol-induced Ca2+-responses were shifted to the right. At higher concentrations, propiverine and M-14, but not M-5 and M-6, directly elevated [Ca2+]i. These results were confirmed for propiverine in human detrusor smooth muscle cells (hDSMC). Propiverine and the three metabolites decreased detrusor contractions evoked by electric field stimulation in a concentration-dependent manner, the order of potency being the same as the order of binding affinity. We conclude that, in comparison with the parent compound, loss of the aliphatic side chain in propiverine metabolites is associated with higher binding affinity to hM1–hM5 receptors and higher functional potency. Change from a tertiary to a secondary amine (M-14) results in lower binding affinity and reduced potency. Oxidation of the nitrogen (M-5) further lowers binding affinity as well as functional potency.

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Acknowledgements

The authors would like to thank Sabine Kirsch for her technical assistance. This project was supported in part by a grant from the “Inno-Regio-Project” BioMet (BMBF, project number 05) from the German Bundesministerium für Bildung und Forschung.

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Authors and Affiliations

  1. Medizinische Fakultät, Institut für Pharmakologie und Toxikologie, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany

    Melinda Wuest, Anke Weiss & Ursula Ravens

  2. Laboratoire de Chimie Biologique et de la Nutrition, Université Libre de Bruxelles, 808 Route de Lennik, 1070, Bruxelles, Belgium

    Magali Waelbroeck

  3. APOGEPHA Arzneimittel GmbH, Kyffhäuser Strasse 27, 01309, Dresden, Germany

    Manfred Braeter

  4. Klinik für Urologie, Diakonissenkrankenhaus Dresden, Holzhofgasse 29, 01099, Dresden, Germany

    Lutz-Ullrich Kelly

  5. Klinik und Poliklinik für Urologie, Universitätsklinikum, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany

    Oliver W. Hakenberg

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  1. Melinda Wuest
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  2. Anke Weiss
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  3. Magali Waelbroeck
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  6. Oliver W. Hakenberg
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  7. Ursula Ravens
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Correspondence to Melinda Wuest.

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Wuest, M., Weiss, A., Waelbroeck, M. et al. Propiverine and metabolites: differences in binding to muscarinic receptors and in functional models of detrusor contraction. Naunyn-Schmied Arch Pharmacol 374, 87–97 (2006). https://doi.org/10.1007/s00210-006-0103-0

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  • DOI: https://doi.org/10.1007/s00210-006-0103-0

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