Pharmacological studies with a nonpeptidic, delta-opioid (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082).

Abstract

In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED50=1.9 (0.7-5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED80 of (-)-NIH 11082 in the PPQ test [AD50=0.75 (0.26-2.20) mg/kg, s.c]. beta-Funaltrexamine and nor-binaltorphimine, selective mu- and kappa-receptor antagonists, respectively, were inactive versus the ED80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.

• Authors: Mario D Aceto, Everette L May, Louis S Harris, Edward R Bowman, Charles D Cook
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 566 Issue 1-3 Pg. 88-93 (Jul 02 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17434480 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride
• Analgesics, Opioid
• Benzomorphans
• Narcotic Antagonists
• Receptors, Opioid, delta
• Naltrexone
• naltrindole

Topics

• Analgesics, Opioid (pharmacology)
• Animals
• Arthritis, Experimental (drug therapy)
• Benzomorphans (chemistry, pharmacology)
• Female
• Hot Temperature
• Macaca mulatta
• Male
• Mice
• Mice, Inbred ICR
• Morphine Dependence
• Naltrexone (analogs & derivatives, pharmacology)
• Narcotic Antagonists (pharmacology)
• Pain (chemically induced, drug therapy)
• Rats
• Rats, Inbred Lew
• Receptors, Opioid, delta (agonists, antagonists & inhibitors)
• Stereoisomerism
• Substance Withdrawal Syndrome (drug therapy)