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

Abstract

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.

Figure 1

18,19-dehydrobuprenorphine: HS-599.

Figure 2

Inhibition of the electrically evoked twitch of guinea-pig ileum preparations. Log-concentration-response curves for the μ-opioid receptor agonist dermorphin, HS-599 and buprenorphine.

Figure 3

Guinea-pig ileum preparation. Log-concentration-response curves for the μ-opioid receptor selective agonist dermorphin, alone or in the presence of different concentrations of HS-599. Dermorphin, slope=1.002 [0.8123 – 1.092]; dermorphin+HS-599 2 nM, slope=0.3838 [0.2888 – 0.4788], P<0.01; dermorphin+HS-599 20 nM, slope=0.06562 [−0.1417 – 0.1454], P<0.01 (Nonlinear regression analysis, Prism).

Figure 4

Inhibition of the electrically evoked twitch of mouse vas deferens preparations. Log-concentration response curves for the δ-opioid receptor selective agonist deltorphin I, alone or in the presence of different HS-599 concentrations. HS-599 shifted the concentration-response curve of deltorphin I to the right without changing the slope (nonlinear regression analysis, Prism): Deltorphin I, slope=1.067 [0.9081 – 1.225]; deltorphin I+HS-599 43 nM, slope=1.351 [1.150 – 1.152]; deltorphin I+HS-599 172 nM, slope=0.9758 [0.8176 – 1.134].

Figure 5

Inhibition of the electrically evoked twitch of rabbit vas deferens preparations. Log-concentration response curves for the κ-opioid receptor selective agonist U-69593, alone or in the presence of different HS-599 concentrations. HS-599 shifted the concentration-response curve of U-69593 to the right without changing the slope (nonlinear regression analysis, Prism): U-69593, slope=1.019 [0.5977 – 1.441]; U69-593+HS-599 2 nM, slope=2.002 [0.7691 – 3.236]; U-69593+HS-599 200 nM, slope=2.387 [1.502 – 3.272].

Figure 6

Dose-response relationship of the antinociception produced by s.c. injection of HS-599, buprenorphine and morphine evaluated with tail-flick test in rats. Curves were fitted to data points and analysed by a linear regression computer program (Tallarida & Murray, 1986). HS-599 AD₅₀=0.11 [0.096 – 0.120] μmol kg⁻¹; buprenorphine AD₅₀=0.219 [0.215 – 0.224] μmol kg⁻¹; morphine AD₅₀=5.29 [1.76 – 15.93] μmol kg⁻¹. Each point represents the mean antinociceptive peak effect of 5 – 8 rats±s.e.mean.

Figure 7

Time course of the antinociception produced by s.c. injection of equianalgesic doses of HS-599 and buprenorphine evaluated by tail-flick test in rats. Each point represents the mean antinociceptive effect of 5 – 8 rats±s.e.mean. Time-response curves have been drawn and analysed by Prism computer program using two-way ANOVA and Bonferroni post-tests.

Figure 8

Antagonism by naloxone (NLX, 3 mg kg⁻¹ s.c.), naltrexone (NLTX, 10 mg kg⁻¹ s.c.), naltrindole (NTI, 20 mg kg⁻¹ s.c.) and nor-Binaltorphimine (nor-BNI, 20 mg kg⁻¹ s.c.) of the antinociception induced by HS-599 (0.2 μmol kg⁻¹ s.c.), in rats (tail-flick test). Each column represents the mean±s.e.mean for 5 – 8 rats in each group. ^**P<0.01 versus the vehicle-pretreated group.

Figure 9

Dose-response curve of the antinociception produced by s.c. administration of HS-599, buprenorphine and morphine in rats (plantar test). Each point represents the mean antinociceptive peak effect of 5 – 8 rats±s.e.mean.

Figure 10

Effect of HS-599, buprenorphine and morphine on conditioned place-preference test in rats. Results are presented as mean±s.e.mean of time (seconds) that rats spent in the drug paired compartment before (control) and after the acquisition of conditioned place-preference (n=6 per group). Results were analysed by a paired two-tailed t-test. All HS-599 values P⩾0.0680 (not significant); buprenorphine, ^**P=0.0021; morphine, ^***P=0.0003.