LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential

doi:10.1016/j.ejphar.2008.02.028

	LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential
	Tao, Yi-Min 1; Li, Qing-Lin 2; Zhang, Cong-Fen 2; Xu, Xue-Jun 1; Chen, Jie 1; Ju, Ya-Wen 1; Chi, Zhi-Qiang1 ; Long, Ya-Qiu 1; Liu, Jing-Gen1
刊名	EUROPEAN JOURNAL OF PHARMACOLOGY
	2008-04-28
卷号	584 期号:2-3 页码:306-311
关键词	kappa-opioid receptor LPK-26 (-)U50,488H morphine physical dependence antinociception
ISSN号	0014-2999
DOI	10.1016/j.ejphar.2008.02.028
文献子类	Article
英文摘要	Analgesics such as morphine cause many side effects including addiction, but K-opioid receptor agonist can produce antinociception without morphine-like side effects. With the aim of developing new and potent analgesics with lower abuse potential, we studied the antinociceptive and physical dependent properties of a derivate of ICI-199441, an analogue of (-)U50,488H, named (2-(3,4-dichloro)-phenyl)-N-methyl-N-[(IS)-1-(2isopropyl)-2-(1-(3-pyrrolinyl))ethyl] acetamides (LPK-26). LPK-26 showed a high affinity to K-opioid receptor with the K-i value of 0.64 nM and,the low affinities to g-opioid receptor and delta-opioid receptor with the K-i values of 1170 nM and > 10,000 nM, respectively. It stimulated [S-35] GTP gamma S binding to G-proteins with an EC50 value of 0.0094 nM. In vivo, LPK-26 was more potent than (-)U50,488H and morphine in analgesia, with the ED50 values of 0.049 mg/kg and 0.0084 mg/kg in hot plat and acetic acid writhing tests, respectively. Moreover, LPK-26 failed to induce physical dependence, but it could suppress naloxone-precipitated jumping in mice when given simultaneously with morphine. Taken together, our results show that LPK-26 is a novel selective K-opioid receptor agonist with highly potent antinociception effects and low physical dependence potential. It may be valuable for the development of analgesic and drug that can be used to reduce morphine-induced physical dependence. (c) 2008 Elsevier B.V All rights reserved.
WOS关键词	PHYSICAL-DEPENDENCE ; OPIATE WITHDRAWAL ; MORPHINE ; ACTIVATION ; MECHANISMS ; EXPRESSION ; TOLERANCE ; U-50,488H ; LIGANDS ; TRK-820
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000255821700013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272935]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第二研究室药物安全性评价中心
通讯作者	Long, Ya-Qiu
作者单位	1.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Anhui Coll Tradit Chinese Med, Hefei 230032, Peoples R China
推荐引用方式 GB/T 7714	Tao, Yi-Min,Li, Qing-Lin,Zhang, Cong-Fen,et al. LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2008,584(2-3):306-311.
APA	Tao, Yi-Min.,Li, Qing-Lin.,Zhang, Cong-Fen.,Xu, Xue-Jun.,Chen, Jie.,...&Liu, Jing-Gen.(2008).LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential.EUROPEAN JOURNAL OF PHARMACOLOGY,584(2-3),306-311.
MLA	Tao, Yi-Min,et al."LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential".EUROPEAN JOURNAL OF PHARMACOLOGY 584.2-3(2008):306-311.