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 (hM(1)-hM(5)) 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 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 respective 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 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 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.