Novel K-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation  

作　　者：Le-shaZHANG Jun WANG Jian-chun CHEN Yi-min TAO Yu-hua WANG Xue-jun XU Jie CHEN Yun-gen XU Tao XI Xiao-wu HU Yu-jun WANG Jing-gen LIU 

机构地区：[1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai 201203, China [2]Biotechnology Center, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China [3]Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China [4]School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China

出　　处：《Acta Pharmacologica Sinica》2015年第5期565-571,共7页中国药理学报（英文版）

摘　　要：Aim： To characterize the pharmacological profiles of a novel K-opioid receptor agonist MB-1C-OH. Methods： [3H]diprenorphine binding and [35S]GTPyS binding assays were performed to determine the agonistic properties of MB-lC-OH Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. Results： In [3H]diprenorphine binding assay, MB-lC-OH did not bind to p- and 6-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor （K1=35 nmol/L）. In [35S]GTPγS binding assay, the compound had an Emax of 98% and an ECso of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-lC-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test （ED50=0.39 mg/kg）, which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-lC-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase （ED50=0.87 mg/kg）. In addition, the sedation or depression actions of MB-lC-OH were about 3-fold weaker than those of the classical K agonist （-）U50,488H. Conclusion： MB-1C-OH is a novel K-opioid receptor agonist that produces potent antinociception causing less sedation and depression.Aim： To characterize the pharmacological profiles of a novel K-opioid receptor agonist MB-1C-OH. Methods： [3H]diprenorphine binding and [35S]GTPyS binding assays were performed to determine the agonistic properties of MB-lC-OH Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. Results： In [3H]diprenorphine binding assay, MB-lC-OH did not bind to p- and 6-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor （K1=35 nmol/L）. In [35S]GTPγS binding assay, the compound had an Emax of 98% and an ECso of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-lC-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test （ED50=0.39 mg/kg）, which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-lC-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase （ED50=0.87 mg/kg）. In addition, the sedation or depression actions of MB-lC-OH were about 3-fold weaker than those of the classical K agonist （-）U50,488H. Conclusion： MB-1C-OH is a novel K-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

关 键 词：K-opioid receptor MB-1C-OH （-）U50 488H Nor-BNI MORPHINE pain acetic acid-induced writhing formalin test DEPRESSION SEDATION 

分 类 号：Q593.2[生物学—生物化学] R749.4[医药卫生—神经病学与精神病学]