Structure-antitussive activity relationships of naltrindole derivatives. Identification of novel and potent antitussive agents

We have previously reported antitussive effects of naltrindole (NTI), a typical 6 opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104,uglk- and 1840 pg[kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has p agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a (5 opioid antagonist, its derivatives have potential as highly potent antitussives, free from the p 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 highiy potent new compound, (5R,9R, I 3S, 14S)- I 7-cyclopropylmethyl6,7-d idehydro-4,5 -epoxy -5',6'-dihydro-3 -meth oxy-4'H-pyrrolo [3,2, 1 -ijlquinolino[2', 1': 6,7] morphinan- 14ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40,uglkg).