Structure activity relationship studies with hypothalamic peptide hormones III. Effect of melanotropin-release inhibiting factor and analogs on tolerance to morphine in the rat.
Structure activity relationship studies with hypothalamic peptide hormones III. Effect of melanotropin-release inhibiting factor and analogs on tolerance to morphine in the rat.
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下丘脑肽激素的结构活性关系研究III．
DOI：
10.1016/0028-3908(82)90084-3
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发表时间：
1982
影响因子：
4.7
通讯作者：
Kim,HS
中科院分区：
文献类型：
--
作者：
Bhargava,HN;Kim,HS
研究了几种促黑素释放抑制因子（MIF, Pro-Leu-Gly-NH2）类似物对雄性Sprague-Dawley大鼠对吗啡的高温、低温和催化作用的耐受性的影响。检测的类似物包括Pro-Gly- gly - nh2 (I)、Pro-Val-Gly-NH2（II）、Pro-Leu-β-Ala-NH2 （III）、Pro-Leu- gly - nhch3 （IV）、Pro-Leu- nh2 (V)和cyclo (Pro-Gly) （VI）。在3天的时间内，皮下植入4个吗啡颗粒（每个含有75 mg的游离吗啡碱），以培养对吗啡药理作用的耐受性。以10 μ mol/kg剂量同时皮下给药上述任一肽（i至vi）不会改变对吗啡诱导的高热、低温或猝厥的耐受性。然而，等量的MIF抑制了吗啡耐受性的发展。用这些肽治疗并没有改变吗啡在脑和血浆中的分布。由此可见，MIF对吗啡耐受产生抑制作用的结构要求非常严格，MIF结构的以下修饰导致活性丧失(a)以Gly或Val取代Leu (b)以Gly- nhch3或β-Ala-NH2取代Gly- nh2 (c)去除Gly， (d)去除Leu后再进行Pro-Gly的环化。
The effects of several analogs of melanotropin-release inhibiting factor (MIF, Pro-Leu-Gly-NH2) on the development of tolerance to the hyperthermic, hypothermic and cataleptic actions of morphine were investigated in male Sprague-Dawley rats. The analogs that were examined included, Pro-Gly-Gly-NH2(I), Pro-Val-Gly-NH2(II), Pro-Leu-β-Ala-NH2, (III), Pro-Leu-Gly-NHCH3(IV), Pro-Leu-NH2(V) and cyclo (Pro-Gly) (VI). Subcutaneous implantation of four morphine pellets (each containing 75 mg of morphine free base) during a 3-day period was used to develop tolerance to the pharmacological effects of morphine. Concurrent daily subcutaneous administration of any of the above peptides (IthroughVI) at a 10 μ mol/kg dose did not modify the development of tolerance to morphine-induced hyperthermia, hypothermia or catalepsy. The development of tolerance to morphine was, however, inhibited by equivalent doses of MIF. Treatment with these peptides did not alter the distribution of morphine in brain and plasma. It is concluded that the structural requirements for the inhibitory effect of MIF on the development of tolerance to morphine are very strict and that the following modifications in the structure of MIF result in the loss of activity (a) substitution of Gly or Val in place of Leu (b) replacement of Gly-NH2with Gly-NHCH3or β-Ala-NH2(c) removal of Gly, and (d) removal of Leu followed by cyclization of Pro-Gly.