naltrindole and Cough

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).

Topics: Alkylation; Animals; Antitussive Agents; Capsaicin; CHO Cells; Cough; Cricetinae; Cricetulus; Male; Mice; Molecular Structure; Naltrexone; Rats; Structure-Activity Relationship

We have previously reported on antitussive effect of (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(1b) methanesulfonate (TRK-850), a selective delta opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical delta opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED(50) values of NTI and compound 1b by intraperitoneal injections were 104 microg/kg and 2.07 microg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8'-fluoro-5',6'-dihydro-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851).

Topics: Administration, Oral; Animals; Antitussive Agents; Capsaicin; Cough; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Male; Mice; Mice, Inbred Strains; Molecular Conformation; Naltrexone; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Stereoisomerism; Structure-Activity Relationship

We examined the effect of [Met5]enkephalin-Arg6-Phe7 (MEAP) on the capsaicin-induced cough reflex in mice. Intracerebroventricular administration of MEAP significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of MEAP was blocked by nor-binaltorphimine, a selective kappa-opioid receptor antagonist. However, beta-funaltrexamine, a mu-opioid receptor antagonist, had no effect on the antitussive effect of MEAP. On the other hand, the antinociceptive effect of MEAP, as determined in the tail-flick test, was blocked by both nor-binaltorphimine and beta-funaltrexamine. Naltrindole, a delta-opioid receptor antagonist, had no effect on either the antitussive effect or the antinociceptive effect of MEAP. These data suggest that MEAP exerts its antitussive effect in mice through the stimulation of kappa-opioid receptors, whereas the antinociceptive effect of MEAP is mediated through the simulation of both kappa- and mu-opioid receptors.

Topics: Animals; Antitussive Agents; Capsaicin; Cough; Dose-Response Relationship, Drug; Enkephalin, Methionine; Injections, Intraventricular; Male; Mice; Naltrexone; Narcotic Antagonists; Receptors, Opioid, kappa; Receptors, Opioid, mu

The effects of naltrindole, a selective delta-opioid receptor antagonist, on the capsaicin-induced cough reflex in mice and rats were studied. Intraperitoneal administration of naltrindole decreased the number of coughs both in mice and rats dose dependently. The cough-depressant effects reached a peak 15 min after the administration of naltrindole and lasted more than 120 min. Pretreatment with [D-Pen2,D-Pen5]enkephalin, a selective delta-opioid receptor agonist, partially but significantly reduced the antitussive effect of naltrindole. Blockade of kappa-opioid receptors by pretreatment with nor-binaltorphimine also partially antagonized the antitussive effect of naltrindole. However, the antitussive effect of naltrindole was not antagonized by beta-funaltrexamine, a selective mu-opioid receptor antagonist. Thus, it is possible that the antitussive effect of naltrindole may be mediated, in part, by kappa-opioid receptors. The present results provide evidence for the development of delta-opioid antagonists, especially naltrindole, for use as antitussive drugs.

Topics: Animals; Antitussive Agents; Capsaicin; Cough; Drug Interactions; Endorphins; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa

We examined the effect of [D-Ala2]deltorphin II, a selective delta 2-opioid receptor agonist, on the antitussive effect of [D-Ala2, MePhe4,Gly-ol5]enkephalin (DAMGO), a selective mu-opioid receptor agonist. [D-Ala2]deltorphin (3 nmol i.c.v.) had no significant effect on the number of coughs. However, upon i.c.v. pretreatment with [D-Ala2]deltorphin II (3 nmol) the antitussive activity of DAMGO (0.03 nmol) was significantly enhanced. The enhancement of the antitussive activity of DAMGO caused by [D-Ala2]deltorphin II was prevented by a benzofuran derivative of naltrindole (0.1 mg/kg s.c.), a selective delta 2-opioid receptor antagonist. These results suggest that delta 2-opioid receptors may play a synergistic role in antitussive processes that are mediated by mu-opioid receptors.

Topics: Animals; Antitussive Agents; Cough; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Oligopeptides; Receptors, Opioid, delta; Receptors, Opioid, mu

When co-administered intracisternally, the selective delta-opioid agonist [D-Pen2,5]enkephalin (DPDPE), which had no significant effect on the cough reflex, consistently and significantly decreased the antitussive potencies of kappa-receptor agonists, U-50,488H and U-62,066E. The decrease in the antitussive effects of these kappa-receptor agonists caused by DPDPE were prevented by selective delta receptor antagonist, naltrindole. These results suggest that delta receptors may play an inhibitory role in antitussive processes that are mediated by the kappa-receptors.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antitussive Agents; Cough; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Indoles; Male; Morphinans; Naltrexone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Reflex

Effects of selective mu and delta receptor agonists on capsaicin-induced cough reflex in rats were studied. Intracisternal injection (i.cist.) of a selective mu receptor agonist [D-Ala2,Mephe4,Gly-ol5]enkephalin (DAMGO) produced dose-related depression of coughs over the 0.003-0.03 nmol dose range. The antitussive potency of DAMGO was 100-fold more potent than morphine. The antitussive effects of DAMGO and morphine were significantly reduced by naloxone (1 nmol i.cist.). The selective delta receptor agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), at a dose of 10 nmol (i.cist.), had no significant effect on the number of coughs. When co-administered i.cist., DPDPE (10 nmol) consistently and significantly decreased the antitussive potencies of DAMGO and morphine. The decrease in the antitussive effects of DAMGO and morphine caused by DPDPE were prevented by selective delta receptor antagonist, naltrindole (3 nmol). These results suggest that the antitussive effects of opioids are mediated predominantly by mu receptors, and delta receptors may play an inhibitory role in antitussive processes that are mediated by the mu receptors.

Topics: Aerosols; Animals; Antitussive Agents; Capsaicin; Cisterna Magna; Cough; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Indoles; Injections; Male; Morphinans; Morphine; Naltrexone; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu