Pharmacological Characterization of ATPM [(-)-3-Amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed kappa-Agonist and mu-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

doi:10.1124/jpet.108.142802

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	Pharmacological Characterization of ATPM [(-)-3-Amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed kappa-Agonist and mu-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior
	Wang, Yu-Jun1 ; Tao, Yi-Min 3; Li, Fu-Ying 3; Wang, Yu-Hua 3; Xu, Xue-Jun 3; Chen, Jie 3; Cao, Ying-Lin 1; Chi, Zhi-Qiang3 ; Neumeyer, John L.2; Zhang, Ao3
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2009-04
卷号	329 期号:1 页码:306-313
ISSN号	0022-3565
DOI	10.1124/jpet.108.142802
文献子类	Article
英文摘要	ATPM [(-)-3-amino-thiazolo[5,4- b]- N- cyclopropylmethylmorphinan hydrochloride] was found to have mixed kappa- and mu-opioid activity and identified to act as a full kappa-agonist and a partial mu-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by kappa- and mu-, but not delta-opioid, receptors. In addition to its agonist profile on the mu-receptor, ATPM also acted as a mu-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED50 value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed kappa-agonist and mu-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. kappa-Agonists with some mu-activity appear to offer some advantages over selective kappa-agonists for the treatment of heroin abuse.
资助项目	Ministry of Science and Technology of China[G2003CB515400] ; Ministry of Science and Technology of China[2007CB935804] ; Ministry of Science and Technology of China[30772625] ; National Natural Science Foundation of China[30425002] ; Chinese National Science Foundation[06ZR14102] ; Chinese Academy of Sciences[KSCXI/YW/R/68] ; National Institutes of Health National Institute on Drug Abuse[DA-014251]
WOS关键词	OPIOID RECEPTOR AGONIST ; RHESUS-MONKEYS ; POTENTIAL PHARMACOTHERAPEUTICS ; COCAINE DISCRIMINATION ; BINDING-AFFINITY ; RATS ; MICE ; TRK-820 ; AGONISTS/ANTAGONISTS ; DERIVATIVES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000264708200034
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279284]
专题	药理学第二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
通讯作者	Liu, Jing-Gen
作者单位	1.Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang, Peoples R China; 2.Harvard Univ, Sch Med, McLean Hosp, Alcohol & Drug Abuse Res Ctr, Cambridge, MA 02138 USA 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Wang, Yu-Jun,Tao, Yi-Min,Li, Fu-Ying,et al. Pharmacological Characterization of ATPM [(-)-3-Amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed kappa-Agonist and mu-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2009,329(1):306-313.
APA	Wang, Yu-Jun.,Tao, Yi-Min.,Li, Fu-Ying.,Wang, Yu-Hua.,Xu, Xue-Jun.,...&Liu, Jing-Gen.(2009).Pharmacological Characterization of ATPM [(-)-3-Amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed kappa-Agonist and mu-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,329(1),306-313.
MLA	Wang, Yu-Jun,et al."Pharmacological Characterization of ATPM [(-)-3-Amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed kappa-Agonist and mu-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 329.1(2009):306-313.