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 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).
Sakami
Satoshi
S
Pharmaceutical Research Laboratories, Toray Industries, Inc, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Maeda
Masayuki
M
Kawai
Koji
K
Aoki
Takumi
T
Kawamura
Kuniaki
K
Fujii
Hideaki
H
Hasebe
Ko
K
Nakajima
Mayumi
M
Endo
Takashi
T
Ueno
Shinya
S
Ito
Tsuyoshi
T
Kamei
Junzo
J
Nagase
Hiroshi
H
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
D000996:Antitussive Agents; D009271:Naltrexone; C055382:naltrindole; D002211:Capsaicin