Tolterodine and its Active 5‐Hydroxymethyl Metabolite: Pure Muscarinic Receptor Antagonists

Tolterodine and its major active 5-hydroxymethyl metabolite (5-HM) are potent muscarinic receptor antagonists that show selectivity for the urinary bladder over salivary glands in vivo. This tissue selectivity cannot be attributed to muscarinic receptor subtype selectivity, since both compounds are non-selective with respect to the M 1 -M 5 receptor subtypes. The aim of the present in vitro study was to determine the specificity of tolterodine and 5-HM for muscarinic receptors compared to other potential cellular targets. Carbachol-induced contractions of isolated guinea pig bladder were effectively inhibited by tolterodine (IC 50 14 nM) and 5-HM (IC 50 5.7 nM). Tolterodine and 5-HM were weak inhibitors of effects mediated by α-adrenergic receptors (rat portal vein), histamine receptors (guinea pig ileum) and calcium channels (guinea pig potassium-depolarised urinary bladder, spontaneously beating right atria and electrically-driven right papillary muscle). The IC 50 values were in the μM range and the antimuscarinic potency of tolterodine was 27, 200 and 370-485 times higher, respectively, than its potency in blocking histamine receptors, α-adrenoceptors and calcium channels. The active metabolite, 5-HM, was >900 times less potent at these sites than at bladder muscarinic receptors. Radioligand binding data on 54 different receptors and binding sites showed that tolterodine and 5-HM bind with significant affinity only at muscarinic receptors. In conclusion, the results of the present study indicate that both tolterodine and 5-HM are specific muscarinic receptor antagonists. The tissue selectivity of these agents in vivo cannot therefore be explained by secondary pharmacological actions.