Probes for narcotic receptor mediated phenomena. 13. Potential irreversible narcotic antagonist-based ligands derived from 6,14-endo-ethenotetrahydronororipavine with 7-(methoxyfumaroyl)amino, (bromoacetyl)amino, or isothiocyanate electrophiles: chemistry, biochemistry, and pharmacology.
N-Allyl-, N-(cyclopropylmethyl)-, and N-propyl-endo-ethenotetrahydronororipavines (N-substituted 6,14-endo-etheno-4,5-epoxy-3-hydroxy-6-methoxymorphinans) were synthesized with potential acylating or alkylating moieties at the C-7 position (isothiocyanato, (bromoacetyl)amino, and (methoxyfumaroyl)amino) and examined in vivo for their narcotic agonist and antagonist activities and for their ability to interact with opioid receptors in vitro. The N-(cyclopropylmethyl)-substituted compounds were found to have the highest affinity for opioid receptors among these N-substituted compounds, although all of them were found to be reasonably potent narcotic antagonists in the mouse tail flick vs. morphine assay. Their in vivo potency ranged from 1/8 to 4 times that of nalorphine on intravenous injection in mice. Rat brain membrane binding studies indicated that the compounds interacted with opioid receptors with potencies that ranged from 0.5 times that of morphine (8c, 9c, and 10c) to 0.017 that of morphine (8b). Among the compounds studied here, only the previously reported isothiocyanato compound (10c) and (methoxyfumaroyl)amino compound (8c) interacted irreversibly and selectively with mu or delta opioid receptors, respectively, in assays using NG108-15 neuroblastoma-glioma hybrid cells and/or in a rat brain membrane preparation. Both 8c and 10c were found to interact irreversibly, to a limited extent, with kappa opioid sites in rat brain membranes in which the mu and delta opioid receptors were depleted by interaction with the mu-selective irreversible ligand BIT and the delta-selective irreversible ligand FIT. Neither compound showed irreversible actions in the electrically stimulated mouse vas deferens preparation.
D000818:Animals; D001921:Brain / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives*; D005283:Fentanyl / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D017879:Isothiocyanates; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship; D013797:Thebaine / Q000031:analogs & derivatives*; D013861:Thiocyanates / Q000494:pharmacology
D017879:Isothiocyanates; D008024:Ligands; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013861:Thiocyanates; D013797:Thebaine; C037152:isothiocyanic acid; D004743:Enkephalin, Leucine; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; C037091:fentanyl isothiocyanate; C042097:2-(4-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidazole; C037669:endo-ethenotetrahydrooripavine; D005283:Fentanyl