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

摘要

class="enumerated" style="list-style-type:decimal">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 μ-opioid antagonists naloxone and naltrexone antagonized HS-599 antinociception the δ-opioid antagonist naltrindole and the κ-opioid antagonist nor-binaltorphimine did not.Unlike buprenorphine and morphine, HS-599 never induced conditioned place-preference in rats.In radioligand binding assays, compared with buprenorphine HS-599 had 3 fold higher μ-opioid receptor affinity but lower δ- and κ-opioid receptor affinity.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 μ-opioid receptor agonist dermorphin, it behaved as a non-equilibrium antagonist. Conversely, in mouse vas deferens (rich in δ-opioid receptors) and rabbit vas deferens preparations (rich in κ-opioid receptors) HS-599 acted as a pure equilibrium antagonist, shifting the log-concentration-response curves of the δ-opioid agonist deltorphin I and the κ-opioid agonist U-69593 to the right.In conclusion, HS-599 is a novel buprenorphine derivative with higher affinity, selectivity and potency than the parent compound, for μ-opioid receptors. It produces intense and long-lasting antinociception and does not induce place-preference in rats.