title: Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland.
abstract: Imidafenacin (CAS 170105-16-5, KRP-197, ONO-8025) is an antagonist for the muscarinic acetylcholine (ACh) receptor currently under development for the treatment of overactive bladder. Affinities of imidafenacin and other drugs for muscarinic ACh receptor subtypes were investigated by examining inhibitory effects on ACh release in the rat urinary bladder and K+ efflux in the rat salivary gland in functional and binding assays. In the functional assay, imidafenacin had higher affnities for M3 and M1 receptors than for the M2 receptor. In contrast, metabolites of imidafenacin (M-2, M-4 and M-9) had low affinities for muscarinic ACh receptor subtypes. Darifenacin had selectivity for the M3 receptor, while propiverine, tolterodine and oxybutynin had no selectivity for muscarinic ACh receptors. In carbamylcholine (CCh)-induced contraction in the urinary bladder, imidafenacin, propiverine, tolterodine and oxybutynin had affinities similar to those for the M3 receptor in the ileum. In the binding assay for human muscarinic ACh receptor subtypes, imidafenacin had higher affinities for m3 and m1 receptors than for m2 receptor, but tolterodine had no selectivity for m1, m2 and m3 receptors. In ACh release in the urinary bladder, inhibitory effects of imidafenacin, tolterodine, oxybutynin and darifenacin seemed to be partially mediated by the M1 receptor. In ACh-induced and electrical stimulation-induced K+ efflux from the salivary gland, inhibitory effects (IC50) of imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin might be closely related to those for the M3 receptor in the ileum. These results suggest that imidafenacin more strongly antagonizes cholinomimetics on M3 and M1 receptors than on the M2 receptor. Moreover, imidafenacin seems to inhibit the contraction of the bladder smooth muscle by mediating antagonism to the M3 receptor and to regulate ACh release by mediating prejunctional facilitatory M1 receptor. Imidafenacin also inhibited K+ efflux from the salivary gland mainly by mediating the M3 receptor. Therefore, imidafenacin will have higher affinities for M3 and M1 receptors and higher selectivity for the urinary bladder than for the salivary gland.
authors.affiliation: Research Department I, Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan. fumiyoshi.kobayashi@mb.kyorin-pharm.co.jp
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Kobayashi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yageta
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Segawa
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsuzawa
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000187:drug effects; D043585:Receptor, Muscarinic M2 / Q000187:drug effects; D043587:Receptor, Muscarinic M3 / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012469:Salivary Glands / Q000187:drug effects* / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism*; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D018680:Cholinergic Antagonists; D007093:Imidazoles; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D002217:Carbachol; D000109:Acetylcholine; D011188:Potassium; C120953:imidafenacin