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Anticholinergic effects of cis- and trans-isomers of two metabolites of propiverine

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Abstract

The muscarinic receptor antagonist propiverine used for therapy of overactive bladder undergoes first pass metabolism, leading to several active metabolites, which affect muscarinic receptors and L-type Ca2+ channels with different potencies. M-5, the major metabolite in blood, and M-6 can be synthesized as cis- and trans-isomers. We systematically investigated the pharmacodynamic profiles of the isomers on detrusor contractile function. In murine and porcine detrusor, the effects of the derivatives were examined on contractions induced by electric field stimulation (EFS), cumulatively increasing concentrations of carbachol or high KCl concentration. EFS contractions were concentration-dependently reduced by the M-5 and M-6 isomers although to a different extent. M-5 cis was slightly more potent than M-5 trans , but the differences did not reach statistical significance. M-6 cis was significantly more potent than M-6 trans . Responses to carbachol were antagonized by all compounds due to rightward shifts of the concentration–response curves, but only M-5 trans also significantly reduced the maximum response. pK B values obtained with Schild plot analysis indicated slightly higher potency for M-6 cis than M-6 trans . Ca2+ influx-dependent contractions elicited by K+ depolarization were less impaired by low concentrations of the M-6 isomers, but strongly suppressed by 100 µM of the M-5 isomers, suggesting an additional effect of the two M-5 isomers on Ca2+ influx. All investigated isomers of M-5 and M-6 are biologically active in reducing detrusor contraction in animal tissue. While M-5cis, M-6 cis , and M-6 trans possess surmountable or partially surmountable antagonistic properties at muscarinic receptors, M-5 trans is a strong non-competitive antagonist. However, at higher concentration ranges, all four compounds seem to have additional effects on Ca2+ influx.

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Acknowledgments

We thank Maria Feilmeier and Sabine Kirsch for their excellent technical help.

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Authors and Affiliations

  1. Department of Urology, University Hospital “Carl Gustav Carus”, Dresden University of Technology, Fetscherstrasse 74, 01307, Dresden, Germany

    Stefan Propping, Marc-Oliver Grimm & Manfred P. Wirth

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

    Manfred Braeter

  3. Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Fetscherstrasse 74, 01307, Dresden, Germany

    Ursula Ravens

  4. Department of Oncology, University of Alberta–Cross Cancer Institute, 11560 University Ave, Edmonton, AB, T6G 1Z2, Canada

    Melinda Wuest

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  1. Stefan Propping
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  2. Manfred Braeter
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  3. Marc-Oliver Grimm
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  4. Manfred P. Wirth
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  5. Ursula Ravens
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  6. Melinda Wuest
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Correspondence to Stefan Propping.

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Propping, S., Braeter, M., Grimm, MO. et al. Anticholinergic effects of cis- and trans-isomers of two metabolites of propiverine. Naunyn-Schmied Arch Pharmacol 381, 329–338 (2010). https://doi.org/10.1007/s00210-010-0493-x

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  • DOI: https://doi.org/10.1007/s00210-010-0493-x

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