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Novel selective κ agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion

Abstract

SLL-039 (N-cyclopropylmethyl-7α−4′-(N’-benzoyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) and SLL-1206 (N-cyclopropylmethyl-7α−3′-(p-methoxybenzyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) are two 4,5-epoxymorphinan-based high selective κ receptor agonists that we recently discovered. In the present study we characterized their pharmacological properties in comparison with arylacetamide-based typical κ agonist U50,488H. We showed that both SLL-039 and SLL-1206 produced potent and long-lasting antinociceptive actions in three different rodent models of pain via activation of κ opioid receptor. In hot-plate assay, the antinociceptive potency of SLL-039 and SLL-1206 increased about 11-and 17.3-fold compared to U50,488H and morphine, respectively, with ED50 values of 0.4 mg/kg. Following repeated administration, SLL-1206, SLL-039, and U50,488H all developed analgesic tolerance tested in hot-plate assay. U50,488H and SLL-039 produced antipruritic effects in a dose-dependent manner, whereas SLL-1206 displayed some antipruritic effects only at very low doses. In addition, SLL-1206 was capable of decreasing morphine-induced physical dependence. More importantly, SLL-039 and SLL-1206 at effective analgesic doses did not cause sedation and conditioned place aversion (CPA), whereas U50,488H did. In comparison with SLL-039, SLL-1206 caused similar antinociceptive responses, but fewer sedation and CPA. In conclusion, our results suggest that SLL-039 and SLL-1206 have potential to be developed as novel analgesic agents, and 4,5-expoxymorphinan scaffold is an attractive structure for the development of selective κ agonists with fewer side effects.

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Fig. 1: Chemical structures of SLL-039, SLL-1206, and U50,488H.
Fig. 2: The antinociceptive effects of SLL-039 and SLL-1206 were evaluated in three models.
Fig. 3: The time courses for the antinociceptive effects of SLL-039 and SLL-1206 (i.p.) in the hot plate test.
Fig. 4: Effects of nor-BNI and β-FNA on SLL-1206-induced antinociception in the abdominal constriction test.
Fig. 5: Development of tolerance to U50,488H, SLL-039 and SLL-1206 -induced antinociception in the hot-plate test.
Fig. 6: The anti-scratching effects of U50,488H, SLL-039 and SLL-1206 in response to administration of chloroquine diphosphate.
Fig. 7: The sedative effects of SLL-039, SLL-1206 and U50,488H in the rotorod test.
Fig. 8: SLL-039, SLL-1206, or U50, 488H produced conditioned place aversion (CPA).
Fig. 9: Effects of SLL-1206 on naloxone-precipitated physical dependence induced by chronic morphine application.
Fig. 10: The effects of SLL-1206 on chronic morphine induced conditioned place preference (CPP).

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Acknowledgements

This research was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDA12040319 to JGL) and National Natural Science Foundation of China (Grant 81773710 to YJW and 82030112 to JGL), and the Youth Innovation Promotion Association of the Chinese Academy of Sciences (Grant 2017334 to YJW).

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JGL, YJW, WL, and LMS designed the experiments. YYW and YM performed the experiments with the assistance of SYY, JRC, and JC. LHK and XL synthesized compounds. YYW, YM, and YJW performed the statistical data analysis. YYW and YJW written this manuscript. JGL, WL, and LMS revised this manuscript.

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Correspondence to Wei Li, Yu-jun Wang, Li-ming Shao or Jing-gen Liu.

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Wei, Yy., Ma, Y., Yao, Sy. et al. Novel selective κ agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00761-x

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Keywords

  • κ-opioid receptor agonist
  • 4,5-expoxymorphinan
  • antinociception
  • conditioned place aversion
  • sedation
  • U50,488H
  • morphine
  • Nor-BNI
  • β-FNA

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