Sakami Satoshi, Maeda Masayuki, Kawai Koji, Aoki Takumi, Kawamura Kuniaki, Fujii Hideaki, Hasebe Ko, Nakajima Mayumi, Endo Takashi, Ueno Shinya, Ito Tsuyoshi, Kamei Junzo, Nagase Hiroshi
Pharmaceutical Research Laboratories, Toray Industries, Inc, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
J Med Chem. 2008 Aug 14;51(15):4404-11. doi: 10.1021/jm701440h. Epub 2008 Jul 19.
We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).
我们之前报道过典型的δ阿片受体拮抗剂纳曲吲哚（NTI）在大鼠模型中的镇咳作用。腹腔注射和口服NTI的半数有效量（ED50）分别为104μg/kg和1840μg/kg，与可待因相当。可待因是最可靠的中枢性镇咳药物之一，具有微激动剂活性，因此具有与吗啡相同的副作用，如便秘、成瘾和呼吸抑制。由于NTI是一种δ阿片拮抗剂，其衍生物有潜力成为高效镇咳药，且无μ阿片激动剂的副作用。我们试图优化NTI衍生物以开发新型镇咳剂。基于对烷基取代NTI衍生物的结构-镇咳活性关系的研究，我们设计了具有额外稠环结构的NTI衍生物。作为临床候选药物，我们确定了一种高效新化合物，即甲磺酸盐（TRK-850）形式的(5R,9R,13S,14S)-17-环丙基甲基-6,7-二脱氢-4,5-环氧-5',6'-二氢-3-甲氧基-4'H-吡咯并[3,2,1-ij]喹啉并[2',1':6,7]吗啡喃-14-醇（5b），其口服给药时也有效（ED50为6.40μg/kg）。
