Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile

doi:10.1021/acs.jmedchem.1c01082

	Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile
	He, Qian 1; Wei, Yuanyuan 2,3,4; Liu, Xiao 1; Ye, Rongrong 5; Kong, Linghui 1; Li, Zixiang 1; Jiang, Shuang 6; Yu, Linqian 1; Chai, Jingrui 2,3; Xie, Qiong 1
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-08-26
卷号	64 期号:16 页码:12414-12433
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c01082
通讯作者	Wang, Yujun(yjwang@mail.simm.ac.cn) ; Li, Wei(wei-li@fudan.edu.cn) ; Liu, Jinggen(jgliu@simm.ac.cn) ; Shao, Liming(limingshao@fudan.edu.cn)
英文摘要	The search for selective kappa opioid receptor (kappa OR) agonists with an improved safety profile is an area of interest in opioid research. In this work, a series of m-substituted analogs were designed, synthesized, and assayed, resulting in the identification of compound 6c (SLL-1206) as a kappa OR agonist with single-digit nanomolar activities. The subtype selectivity of compound 6c appeared to be a consequence of an enormous decrease in the affinity for mu OR and delta OR, rather than a significant increase in the affinity for kappa OR, which was not the case for SLL-039, another selective and potent kappa OR agonist identified in our previous work. Besides reduced central nervous system effects, SLL-1206 exhibited substantially improved physicochemical and pharmacokinetic properties compared with SLL-039, with increases of over 20-fold in aqueous solubility and approximately 40-fold in oral bioavailability in rats.
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040319] ; National Natural Science Foundation of China[81671322] ; National Natural Science Foundation of China[82030112] ; National Natural Science Foundation of China[81773710] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017334]
WOS关键词	MORPHINE-THEBAINE GROUP ; MOLECULAR-REARRANGEMENTS ; EFFICACY ; ANALOGS ; NALFURAFINE ; ORVINOLS ; PAIN ; ANTINOCICEPTION ; DERIVATIVES ; ANALGESICS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000692012400035
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297839]
专题	中国科学院上海药物研究所
通讯作者	Wang, Yujun; Li, Wei; Liu, Jinggen; Shao, Liming
作者单位	1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Collaborat Innovat Ctr Brain Sci, Shanghai 201203, Peoples R China 4.China Pharmaceut Univ, Sch Basic Med Sci & Clin Pharm, Nanjing 210009, Jiangsu, Peoples R China 5.Shanghai Inst Technol, Sch Chem & Environm Engn, Shanghai 201418, Peoples R China 6.Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Peoples R China 7.Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China
推荐引用方式 GB/T 7714	He, Qian,Wei, Yuanyuan,Liu, Xiao,et al. Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(16):12414-12433.
APA	He, Qian.,Wei, Yuanyuan.,Liu, Xiao.,Ye, Rongrong.,Kong, Linghui.,...&Shao, Liming.(2021).Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile.JOURNAL OF MEDICINAL CHEMISTRY,64(16),12414-12433.
MLA	He, Qian,et al."Discovery of an M-Substituted N-Cyclopropylmethyl-7 alpha-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active kappa-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile".JOURNAL OF MEDICINAL CHEMISTRY 64.16(2021):12414-12433.