title: Structure-antitussive activity relationships of naltrindole derivatives. Identification of novel and potent antitussive agents.
abstract: We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu 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, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakami
authors.forename: Masayuki
authors.initials: M
authors.lastname: Maeda
authors.forename: Koji
authors.initials: K
authors.lastname: Kawai
authors.forename: Takumi
authors.initials: T
authors.lastname: Aoki
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Kawamura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Ko
authors.initials: K
authors.lastname: Hasebe
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nakajima
authors.forename: Takashi
authors.initials: T
authors.lastname: Endo
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ito
authors.forename: Junzo
authors.initials: J
authors.lastname: Kamei
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000478:Alkylation; D000818:Animals; D000996:Antitussive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D016466:CHO Cells; D002211:Capsaicin / Q000494:pharmacology; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy; D006224:Cricetinae; D003412:Cricetulus; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000996:Antitussive Agents; D009271:Naltrexone; C055382:naltrindole; D002211:Capsaicin