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 δ opioid receptor antagonist, in a rat model. The ED<sub>50</sub> values of NTI by intraperitoneal and peroral injections were 104 μg/kg and 1840 μg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has μ agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a δ opioid antagonist, its derivatives have potential as highly potent antitussives, free from the μ 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, (5<i>R</i>,9<i>R</i>,13<i>S</i>,14<i>S</i>)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5′,6′-dihydro-3-methoxy-4′<i>H</i>-pyrrolo[3,2,1-<i>ij</i>]quinolino[2′,1′:6,7]morphinan-14-ol (<b>5b</b>) methanesulfonate (TRK-850) which was effective even by oral administration (ED<sub>50</sub> 6.40 μg/kg).