Nagabukuro Hiroshi, Okanishi Satoshi, Imai Shigemitsu, Ishichi Yuji, Ishihara Yuji, Doi Takayuki
Pharmaceutical Research Division, Takeda Chemical Industries, 2-17-85, Jusohonmachi, Yodogawa, Osaka 532-8686, Japan.
Eur J Pharmacol. 2004 Feb 6;485(1-3):299-305. doi: 10.1016/j.ejphar.2003.11.045.
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.
在本研究中，我们研究了新型乙酰胆碱酯酶抑制剂8-[3-[1-[(3-氟苯基)甲基]-4-哌啶基]-1-氧代丙基]-1,2,5,6-四氢-4H-吡咯并[3,2,1-ij]喹啉-4-酮（TAK-802）对乌拉坦麻醉的大鼠和豚鼠中扩张诱导的膀胱节律性收缩的影响。TAK-802能有效抑制人红细胞源性乙酰胆碱酯酶活性，IC(50)值为1.5 nM，其效力分别比两种氨基甲酸酯类乙酰胆碱酯酶抑制剂新斯的明和地斯的明高30倍和250倍。与氨基甲酸酯类乙酰胆碱酯酶抑制剂不同，TAK-802对乙酰胆碱酯酶抑制的选择性高于对丁酰胆碱酯酶的抑制。在一项测量毒蕈碱和烟碱作用的试验中，发现与地斯的明相比，TAK-802对毒蕈碱作用的选择性高于烟碱作用。TAK-802和地斯的明均以剂量依赖性方式增加大鼠和豚鼠的等容膀胱收缩，大鼠的最小有效剂量（MED）分别为静脉注射0.01和0.03 mg/kg，豚鼠分别为静脉注射0.01和0.1 mg/kg。两种药物的作用均被阿托品完全消除。这些结果表明，TAK-802和其他乙酰胆碱酯酶抑制剂可通过提高神经冲动释放的乙酰胆碱的效力来有效增加反射性膀胱收缩。另一方面，毒蕈碱激动剂氨甲酰甲胆碱以1 mg/kg静脉注射时，明显改变了扩张诱导的膀胱收缩模式，且不一定增强协调性良好的膀胱收缩。因此，考虑到TAK-802对毒蕈碱作用有一定选择性，有望用于治疗由逼尿肌收缩功能受损引起的排尿功能障碍。
