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

doi:10.1038/s41401-021-00761-x

	Novel selective kappa agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion
	Wei, Yuan-yuan 1,2; Ma, Yan 2; Yao, Song-yu 2,3; Kong, Ling-hui 4; Liu, Xiao 4; Chai, Jing-rui 2; Chen, Jing 2; Li, Wei 4; Wang, Yu-jun 2; Shao, Li-ming 4
刊名	ACTA PHARMACOLOGICA SINICA
	2021-09-07
页码	11
关键词	kappa-opioid receptor agonist 4,5-expoxymorphinan antinociception conditioned place aversion sedation U50,488H morphine Nor-BNI beta-FNA
ISSN号	1671-4083
DOI	10.1038/s41401-021-00761-x
通讯作者	Li, Wei(wei-li@fudan.edu.cn) ; Wang, Yu-jun(yjwang@mail.simm.ac.cn) ; Shao, Li-ming(limingshao@fudan.edu.cn) ; Liu, Jing-gen(jgliu@simm.ac.cn)
英文摘要	SLL-039 (N-cyclopropylmethyl-7 alpha-4'-(N'-benzoyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) and SLL-1206 (N-cyclopropylmethyl-7 alpha-3'-(p-methoxybenzyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) are two 4,5-epoxymorphinan-based high selective K receptor agonists that we recently discovered. In the present study we characterized their pharmacological properties in comparison with arylacetamide-based typical K 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 K 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 K agonists with fewer side effects.
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040319] ; National Natural Science Foundation of China[81773710] ; National Natural Science Foundation of China[82030112] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017334]
WOS关键词	OPIOID RECEPTOR AGONIST ; PHARMACOLOGICAL CHARACTERIZATION ; NALFURAFINE HYDROCHLORIDE ; HEMODIALYSIS-PATIENTS ; DOUBLE-BLIND ; MU ; SALVINORIN ; TOLERANCE ; MORPHINE ; EFFICACY
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000693489200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297857]
专题	中国科学院上海药物研究所
通讯作者	Li, Wei; Wang, Yu-jun; Shao, Li-ming; Liu, Jing-gen
作者单位	1.China Pharmaceut Univ, Sch Basic Med & Clin Pharm, Nanjing 210009, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 4.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Wei, Yuan-yuan,Ma, Yan,Yao, Song-yu,et al. Novel selective kappa agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion[J]. ACTA PHARMACOLOGICA SINICA,2021:11.
APA	Wei, Yuan-yuan.,Ma, Yan.,Yao, Song-yu.,Kong, Ling-hui.,Liu, Xiao.,...&Liu, Jing-gen.(2021).Novel selective kappa agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion.ACTA PHARMACOLOGICA SINICA,11.
MLA	Wei, Yuan-yuan,et al."Novel selective kappa agonists SLL-039 and SLL-1206 produce potent antinociception with fewer sedation and aversion".ACTA PHARMACOLOGICA SINICA (2021):11.