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 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.