Structure−Antitussive Activity Relationships of Naltrindole Derivatives. Identification of Novel and Potent Antitussive Agents SakamiSatoshi MaedaMasayuki KawaiKoji AokiTakumi KawamuraKuniaki FujiiHideaki HasebeKo NakajimaMayumi EndoTakashi UenoShinya ItoTsuyoshi KameiJunzo NagaseHiroshi 2008 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).