title: Pharmacological effects of imidafenacin (KRP-197/ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task.
abstract: Imidafenacin (CAS 170105-16-5, KRP-197, ONO-8025) has been developed for the treatment of overactive bladder as a new anti-cholinergic with high affinities for muscarinic acetylcholine M3 and M1 receptors. The pharmacological profiles of imidafenacin on the urinary bladder function by determining carbamylcholine (CCh)-induced decrease in bladder capacity and distention-induced rhythmic bladder contraction in conscious rats were investigated. In addition, effects of imidafenacin on CCh-induced salivary secretion and performance in the Morris water maze task in rats were investigated to evaluate side effects, such as dry mouth and cognitive dysfunction in the central nervous system (CNS). Imidafenacin prevented the CCh-induced decrease in bladder capacity dose-dependently with an ID50 of 0.055 mg/kg. On the distention-induced rhythmic bladder contraction, imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects with ID30's of 0.17, 15, 3.0, 3.2 and 0.85 mg/kg, respectively. The rank order of inhibitory potency was: imidafenacin > darifenacin > tolterodine > or = oxybutynin > propiverine. Imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects on the CCh-stimulated salivary secretion with ID50's of 1.5, 14, 15, 4.4 and 1.2 mg/kg, respectively. The rank order of inhibitory potency was: darifenacin > or = imidafenacin > oxybutynin > propiverine > or = tolterodine. Imidafenacin at the doses of 1 and 10 mg/ kg did not affect the escape latencies in the Morris water maze task compared with those in vehicle controls. Oxybutynin at the dose of 100 mg/kg induced a significant increase in the escape latencies, but propiverine at the dose of 100 mg/kg did not induce significant changes. These results suggest that imidafenacin inhibits urinary bladder contraction to a greater extent than the salivary secretion (compared with the M3 receptor selective antagonist, darifenacin, and the non-selective antagonists, propiverine, tolterodine and oxybutynin) or the CNS functions, such as performance in the Morris water maze task (compared with oxybutynin). In conclusion, imidafenacin has organ selectivity for the bladder over the salivary gland, without influence on the central nervous system such as spatial learning and memory.
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: Takanobu
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Eiji
authors.initials: E
authors.lastname: Wakabayashi
authors.forename: Masako
authors.initials: M
authors.lastname: Inoue
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Segawa
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsuzawa
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology* / Q000633:toxicity; D003072:Cognition Disorders / Q000139:chemically induced / Q000523:psychology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D012472:Salivation / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects*
chemical_list: D018680:Cholinergic Antagonists; D007093:Imidazoles; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D002217:Carbachol; D012601:Scopolamine; C120953:imidafenacin