Pharmacological properties of JDTic:: a novel κ-opioid receptor antagonist
Pharmacological properties of JDTic:: a novel κ-opioid receptor antagonist
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DOI：
10.1016/j.ejphar.2004.08.028
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发表时间：
2004-10-06
影响因子：
5
通讯作者：
Harris, LS
中科院分区：
文献类型：
--
作者：
Carroll, I;Thomas, JB;Harris, LS
对(3R)-7-羟基- n -{(1S)-1-{[(3R,4R)-4-（3-羟基苯基）-3,4-二甲基-1-哌替啶基]甲基}-2-甲基丙基}-1,2,3，4-四氢-3-异喹啉-羧酰胺（JDTic），第一个有效的k选择性阿片受体拮抗剂，不是从阿片类化合物中提取的。在小鼠甩尾试验中，皮下注射JDTic （s.c）可阻断抗避孕药活性长达2周。在选择性KOP (kappa)-阿片受体激动剂使用前24 h，分别给予JDTic或s.c.p o, enadoline， AD（50s）分别为4.1和27.3。JDTic与依纳多啉的时间过程研究表明，拮抗剂p.o.活性可达28天。相比之下，JDTic, s.c不能拮抗选择性MOP (mu)-阿片受体激动剂舒芬达的镇痛作用。il.在松鼠猴休克滴定抗感觉试验中，肌注JDTic使反式3,4-二氯- n -甲基- n -（2-[1-吡啶基]环己基）苯乙酰胺（U50,488）的剂量效应曲线向右偏移。在u50,488诱导的利尿大鼠试验中，JDTic, s.c抑制利尿活性的效力大于未加binaltorphamine（未加bni）。因此，JDTic是一种有效的长效和口服选择性kappa-阿片拮抗剂。(C) 2004 Elsevier B.V.版权所有
Biological studies were conducted on (3R)-7-Hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,.4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent K-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP (mu)-opioid receptor agonist, sufentar. il. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist. (C) 2004 Elsevier B.V. All rights reserved.