ORIGINAL ARTICLE Propiverine and metabolites: differences in binding to muscarinic receptors and in functional models of detrusor contraction Melinda Wuest & Anke Weiss & Magali Waelbroeck & Manfred Braeter & Lutz-Ullrich Kelly & Oliver W. Hakenberg & Ursula Ravens Received: 27 June 2006 / Accepted: 2 August 2006 / Published online: 20 October 2006 # Springer-Verlag 2006 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 func- tions, 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 (hM 1 –hM 5 ) expressed in chinese hamster ovary cells, and to examine the effects of these compounds on muscarinic receptor-mediated detrusor function. Propi- verine, M-5, M-6 and M-14 bound to hM 1 –hM 5 receptors with the same order of affinity for all five subtypes: M-6 > propiverine > M-14 > M-5. In HEK-293 cells expressing hM 3 , carbachol-induced release of intracellular Ca 2+ ([Ca 2+ ] i ) was suppressed by propiverine and its metabolites; the respec- tive concentration-response curves for carbachol-induced Ca 2+ -responses were shifted to the right. At higher concentrations, propiverine and M-14, but not M-5 and M-6, directly elevated [Ca 2+ ] i . These results were con- firmed 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 com- pound, loss of the aliphatic side chain in propiverine metabolites is associated with higher binding affinity to hM 1 –hM 5 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. Keywords Propiverine and metabolites . Muscarinic receptors . Calcium . Detrusor contraction Introduction Muscarinic receptor antagonists are the most widely used drugs for the therapy of overactive bladder (OAB) symptoms (Sellers et al. 2001; Andersson et al. 2002; Naunyn-Schmiedeberg’ s Arch Pharmacol (2006) 374:87–97 DOI 10.1007/s00210-006-0103-0 M. Wuest (*) : A. Weiss : U. Ravens Medizinische Fakultät, Institut für Pharmakologie und Toxikologie, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany e-mail: melinda.wuest@tu-dresden.de M. Waelbroeck Laboratoire de Chimie Biologique et de la Nutrition, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Bruxelles, Belgium M. Braeter APOGEPHA Arzneimittel GmbH, Kyffhäuser Strasse 27, 01309 Dresden, Germany L.-U. Kelly Klinik für Urologie, Diakonissenkrankenhaus Dresden, Holzhofgasse 29, 01099 Dresden, Germany O. W. Hakenberg Klinik und Poliklinik für Urologie, Universitätsklinikum, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany