Human Muscarinic Receptor Binding Characteristics of Antimuscarinic Agents to Treat Overactive Bladder.

Purpose: We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors. Materials and Methods: Competitive inhibitory effects of antimuscarinic agents on specific NMS [H] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes. Results: Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N→O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [³H]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M₁ to M₅ receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N→O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N→O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [³H]NMS binding at cell membranes expressing the M₂ vs the M₃ subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N→O) and darifenacin showed 2 to 22 times higher affinity to the M₃ than to the M₂ subtype. Conclusions: Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N→O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland. [Copyright &y& Elsevier]