HS-599: a novel long acting opioid analgesic does not induce place-preference in rats

I When administered subcutaneously HS-599, a new didehydroderivative of bup renorphine (18,19-dehydrobuprenorphine), produced a long-lasting antinocice ptive response in rats. Its potency exceeded twice that of buprenorphine. I n the tail-flick test it acted as a full agonist but in the plantar test on ly as a partial agonist. Whereas the mu -opioid antagonists naloxone and na ltrexone antagonized HS-599 antinociception the delta -opioid antagonist na ltrindole and the kappa -opioid antagonist nor-binaltorphimine did not. 2 U nlike buprenorphine and morphine, HS-599 never induced conditioned place-pr eference in rats. 3 In radioligand binding assays, compared with buprenorph ine HS-599 had 3 fold higher mu -opioid receptor affinity but lower delta- and kappa -opioid receptor affinity. 4 In isolated guinea-pig ileum prepara tions, HS-599 only partially inhibited the electrically-stimulated contract ion, acting as a partial opioid agonist. When tested against the mu -opioid receptor agonist dermorphin, it behaved as a non-equilibrium antagonist. C onversely, in mouse vas deferens (rich in delta -opioid receptors) and rabb it 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 agon ist U-69593 to the right. 5 In conclusion, HS-599 is a novel buprenorphine derivative with higher affinity, selectivity and potency than the parent co mpound, for mu -opioid receptors. It produces intense and long-lasting anti nociception and does not induce place-preference in rats.