• Le-sha Zhang, 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, and Jing-gen Liu.
• 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.
• Acta Pharmacol. Sin. 2015 May 1; 36 (5): 565-71.

AimTo characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH.Methods[(3)H]diprenorphine binding and [(35)S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-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.ResultsIn [(3)H]diprenorphine binding assay, MB-1C-OH did not bind to μ- and δ-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor (Ki=35 nmol/L). In [(35)S]GTPγS binding assay, the compound had an Emax of 98% and an EC50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-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-1C-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-1C-OH were about 3-fold weaker than those of the classical κ agonist (-)U50,488H.ConclusionMB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

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