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

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.British Journal of Pharmacology (2001) 134 , 441–447; doi: 10.1038/sj.bjp.0704280