title: Effects of TAK-802, a novel acetylcholinesterase inhibitor, on distension-induced rhythmic bladder contractions in rats and guinea pigs.
abstract: In the present study, we investigated the effects of 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (TAK-802), a novel acetylcholinesterase inhibitor, on distension-induced rhythmic bladder contractions in urethane-anesthetized rats and guinea pigs. TAK-802 potently inhibited human-erythrocyte-derived acetylcholinesterase activity with an IC(50) value of 1.5 nM, which represented a potency 30 and 250 times greater than that of the two carbamate acetylcholinesterase inhibitors, neostigimine and distigmine, respectively. Unlike the carbamate acetylcholinesterase inhibitors, TAK-802 exhibits high selectivity for acetylcholinesterase inhibition over butyrylcholinesterase inhibition. In an assay conducted to measure the muscarinic and nicotinic actions, TAK-802 was found to exhibit higher selectivity for muscarinic actions over nicotinic actions in comparison to distigmine. Both TAK-802 and distigmine increased isovolumetric bladder contractions in rats and guinea pigs in a dose-dependent manner, with a minimum effective dose (MED) of 0.01 and 0.03 mg/kg i.v., respectively, in rats, and 0.01 and 0.1 mg/kg i.v., respectively, in guinea pigs. The effects of both the drugs were completely abolished by atropine. These results suggest that TAK-802 and other acetylcholinesterase inhibitors can effectively increase reflex bladder contractions by increasing the efficacy of acetylcholine released by nerve impulses. On the other hand, bethanechol, a muscarinic agonist, markedly changed the pattern of distension-induced bladder contractions when administered at the dose of 1 mg/kg i.v., and it did not necessarily augment well-coordinated bladder contractions. Thus, considering that it has some selectivity for muscarinic action, TAK-802 might be expected to be useful in the treatment of voiding dysfunction caused by impaired detrusor contractility.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, 2-17-85, Jusohonmachi, Yodogawa, Osaka 532-8686, Japan. nagabukuro_hiroshi@takeda.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagabukuro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okanishi
authors.forename: Shigemitsu
authors.initials: S
authors.lastname: Imai
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishichi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Doi
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase