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

作　　者：Yuan-yuan Wei Yan Ma Song-yu Yao Ling-hui Kong Xiao Liu Jing-rui Chai Jing Chen Wei Li Yu-jun Wang Li-ming Shao Jing-gen Liu 

机构地区：[1]School of Basic Medicine and Clinical Pharmacy,China Pharmaceutical University,Nanjing 210009,China [2]Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China [4]Department of Medicinal Chemistry,School of Pharmacy,Fudan University,Shanghai 201203,China

出　　处：《Acta Pharmacologica Sinica》2022年第6期1372-1382,共11页中国药理学报（英文版）

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

摘　　要：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 selectiveκreceptor agonists that we recently discovered.In the present study we characterized their pharmacological properties in comparison with arylacetamide-based typicalκagonist 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 ofκopioid 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 selectiveκagonists with fewer side effects.

关 键 词：κ-opioid receptor agonist 45-expoxymorphinan ANTINOCICEPTION conditioned place aversion SEDATION U50488H morphine Nor-BNI β-FNA 

分 类 号：R96[医药卫生—药理学]