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).

Molecular Pharmacology ofδ-Opioid Receptors

“…The 5-isocyanate analog of NTI, 59-NTII, was the first irreversible nonpeptide DOPr antagonist (Portoghese et al, 1990), which produced long-lasting antagonism of the antinociceptive effects of the DOPr2 agonists DSLET and deltorphin II but not of that of the DOPr1 agonist DPDPE (Jiang et al, 1991;Vanderah et al, 1994). The NTI derivative 9R,13S,2,quinolino [29,19:6,7]morphinan-14-ol(1b) methanesulfonate] showed moderate DOPr binding affinity and DOPr partial agonist activity (Sakami et al, 2008b). A TRK-850 analog, TRK-851 [(5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-89-fluoro-59,69-dihydro-49H-pyrrolo[3,2,1-ij]quinolino [29,19:6,7]morphinan-3,14-diol(1c) methanesulfonate], also showed DOPr antagonist properties and was metabolically more stable (Sakami et al, 2008a).…”

Antitussive Indole Alkaloids fromKopsia hainanensis

“…Such conflicting results may be explained by the different pharmacological roles of the two δ1 (inhibitory effects) and δ2 (synergistic effects) opioid receptor subtypes [1,3] and the pharmacology of the δ/µ receptor heteroligomerization [6,7]. In two recent articles, naltrindole analogs TRK-850 and -851 were reported to show promising potential for the development of a novel class of antitussive agents [8,9].…”

Rh(III)-Catalyzed C–H Bond Activation for the Construction of Heterocycles with sp3-Carbon Centers

“…1-Anminoindoline has been widely utilized as a chemical feedstock to access various skeletal motifs existed in numerous commercial drugs [56]. In 2014, Glorious and co-workers revealed an intermolecular catalytic method that can directly access 1-aminoindoline core [57].…”