Structure−Antitussive Activity Relationships of Naltrindole Derivatives. Identification of Novel and Potent Antitussive Agents
Satoshi Sakami
Masayuki Maeda
Koji Kawai
Takumi Aoki
Kuniaki Kawamura
Hideaki Fujii
Ko Hasebe
Mayumi Nakajima
Takashi Endo
Shinya Ueno
Tsuyoshi Ito
Junzo Kamei
Hiroshi Nagase
10.1021/jm701440h.s001
https://acs.figshare.com/articles/journal_contribution/Structure_Antitussive_Activity_Relationships_of_Naltrindole_Derivatives_Identification_of_Novel_and_Potent_Antitussive_Agents/2920933
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).
2008-08-14 00:00:00
δ opioid receptor antagonist
μ opioid agonist side effects
TRK
δ opioid antagonist
NTI derivatives
μ agonist activity
novel antitussive agents
ED 50 values
Potent Antitussive AgentsWe