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

Aim: To characterize the pharmacological profiles of a novel kappa-opioid receptor agonist MB-1C-OH. Methods: [H-3]diprenorphine binding and [S-35]GTP.S 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 [H-3]diprenorphine binding assay, MB-1C-OH did not bind to mu- and delta-opioid receptors at the concentration of 100 mu mol/L, but showed a high affinity for kappa-opioid receptor (kappa(i)=35 nmol/L). In [S-35]GTP gamma S binding assay, the compound had an E-max of 98% and an EC50 of 16.7 nmol/L for kappa-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.-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 kappa agonist (-)U50,488H. Conclusion: MB-1C-OH is a novel kappa-opioid receptor agonist that produces potent antinociception causing less sedation and depression.