Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph.
Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a mu antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.
Jinsmaa
Yunden
Y
Medicinal Chemistry Group, Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Marczak
Ewa D
ED
Balboni
Gianfranco
G
Salvadori
Severo
S
Lazarus
Lawrence H
LH
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008024:Ligands; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
D000701:Analgesics, Opioid; C533065:H-Dmt-Tic-Lys(Z)-NH-CH2-Ph; D008024:Ligands; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C060208:deltorphin I, Ala(2)-; D013004:Somatostatin; D009271:Naltrexone; D009020:Morphine; C055382:naltrindole