HS-599: a novel long acting opioid analgesic does not induce place-preference in rats.
1. When administered subcutaneously HS-599, a new didehydroderivative of buprenorphine (18,19-dehydrobuprenorphine), produced a long-lasting antinociceptive response in rats. Its potency exceeded twice that of buprenorphine. In the tail-flick test it acted as a full agonist but in the plantar test only as a partial agonist. Whereas the mu-opioid antagonists naloxone and naltrexone antagonized HS-599 antinociception the delta-opioid antagonist naltrindole and the kappa-opioid antagonist nor-binaltorphimine did not. 2. Unlike buprenorphine and morphine, HS-599 never induced conditioned place-preference in rats. 3. In radioligand binding assays, compared with buprenorphine HS-599 had 3 fold higher mu-opioid receptor affinity but lower delta- and kappa-opioid receptor affinity. 4. In isolated guinea-pig ileum preparations, HS-599 only partially inhibited the electrically-stimulated contraction, acting as a partial opioid agonist. When tested against the mu-opioid receptor agonist dermorphin, it behaved as a non-equilibrium antagonist. Conversely, in mouse vas deferens (rich in delta-opioid receptors) and rabbit vas deferens preparations (rich in kappa-opioid receptors) HS-599 acted as a pure equilibrium antagonist, shifting the log-concentration-response curves of the delta-opioid agonist deltorphin I and the kappa-opioid agonist U-69593 to the right. 5. In conclusion, HS-599 is a novel buprenorphine derivative with higher affinity, selectivity and potency than the parent compound, for mu-opioid receptors. It produces intense and long-lasting antinociception and does not induce place-preference in rats.
Lattanzi
R
R
Department of Human Physiology and Pharmacology, University 'La Sapienza', P.le Aldo Moro, 5, I-00185 Rome, Italy.
Negri
L
L
Giannini
E
E
Schmidhammer
H
H
Schutz
J
J
Improta
G
G
D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D044482:Benzeneacetamides; D001667:Binding, Competitive / Q000187:drug effects; D002047:Buprenorphine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010146:Pain / Q000517:prevention & control; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D014649:Vas Deferens / Q000378:metabolism
D000701:Analgesics, Opioid; D044482:Benzeneacetamides; C439307:HS 599; D009842:Oligopeptides; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C059567:deltorphin; D002047:Buprenorphine; D009020:Morphine; C045444:U 69593