title: Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation.
abstract: OBJECTIVE
  To 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.
  
  
  RESULTS
  In [(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.
  
  
  CONCLUSIONS
  MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.
authors: 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.
authors: Le-sha
authors: LS
authors: Zhang
authors: 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.
authors: Jun
authors: J
authors: Wang
authors: Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Jian-chun
authors: JC
authors: Chen
authors: 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.
authors: Yi-min
authors: YM
authors: Tao
authors: 1] Biotechnology Center, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China [2] School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China.
authors: Yu-hua
authors: YH
authors: Wang
authors: 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.
authors: Xue-jun
authors: XJ
authors: Xu
authors: 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.
authors: Jie
authors: J
authors: Chen
authors: Biotechnology Center, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors: Yun-gen
authors: YG
authors: Xu
authors: Biotechnology Center, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors: Tao
authors: T
authors: Xi
authors: Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors: Xiao-wu
authors: XW
authors: Hu
authors: 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.
authors: Yu-jun
authors: YJ
authors: Wang
authors: 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.
authors: Jing-gen
authors: JG
authors: Liu
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D016466:CHO Cells; D003412:Cricetulus; D003863:Depression / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D017288:Pain Threshold / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D007546:Isoquinolines; D008024:Ligands; C000604794:MB-1C-OH; D017473:Receptors, Opioid, kappa