LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential

Eur J Pharmacol. 2008 Apr 28;584(2-3):306-11. doi: 10.1016/j.ejphar.2008.02.028. Epub 2008 Feb 19.


Analgesics such as morphine cause many side effects including addiction, but kappa-opioid receptor agonist can produce antinociception without morphine-like side effects. With the aim of developing new and potent analgesics with lower abuse potential, we studied the antinociceptive and physical dependent properties of a derivate of ICI-199441, an analogue of (-)U50,488H, named (2-(3,4-dichloro)-phenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl] acetamides (LPK-26). LPK-26 showed a high affinity to kappa-opioid receptor with the Ki value of 0.64 nM and the low affinities to micro-opioid receptor and delta-opioid receptor with the Ki values of 1170 nM and >10,000 nM, respectively. It stimulated [(35)S]GTPgammaS binding to G-proteins with an EC50 value of 0.0094 nM. In vivo, LPK-26 was more potent than (-)U50,488H and morphine in analgesia, with the ED50 values of 0.049 mg/kg and 0.0084 mg/kg in hot plat and acetic acid writhing tests, respectively. Moreover, LPK-26 failed to induce physical dependence, but it could suppress naloxone-precipitated jumping in mice when given simultaneously with morphine. Taken together, our results show that LPK-26 is a novel selective kappa-opioid receptor agonist with highly potent antinociception effects and low physical dependence potential. It may be valuable for the development of analgesic and drug that can be used to reduce morphine-induced physical dependence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetic Acid
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Hot Temperature / adverse effects
  • Humans
  • Male
  • Mice
  • Motor Activity / drug effects
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Opioid-Related Disorders / prevention & control*
  • Pain / etiology
  • Pain / physiopathology
  • Pain / prevention & control*
  • Pain Measurement
  • Pain Threshold / drug effects*
  • Protein Binding
  • Pyrroles / pharmacology*
  • Rats
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, kappa / genetics
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism
  • Time Factors
  • Transfection


  • Analgesics, Opioid
  • LPK-26
  • Narcotic Antagonists
  • Pyrroles
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Naloxone
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Acetic Acid