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Identification of Novel and Potent Antitussive Agents. 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; |
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[摘要]：We have previously reported antitussive effects of naltrindole (NTI), a typical d opioid receptor antagonist, in a rat model. The ED50 values of NTI by i.p. and peroral injections were 104 mg/kg and 1840 mg/kg, resp., comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has m agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a d opioid antagonist, its derivs. have potential as highly potent antitussives, free from the m opioid agonist side effects. We attempted to optimize the NTI derivs. to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivs., we designed NTI derivs. with extra ring fused structures. As a clin. candidate, we identified a highly potent new compd., (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-d ihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b)(I) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 mg/kg). |
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