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 > oxybu-tynin > 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 > imidafenacin > oxybutynin > propiverine > 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.
Key words
Anti-cholinergics - CAS 170105-16-5 - Imidafenacin - KRP-197 - Morris water maze -
ONO-8025 - Overactive bladder - Salivary gland - Urinary bladder
