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

Analgesics such as morphine cause many side effects including addiction, but K-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-[(IS)-1-(2isopropyl)-2-(1-(3-pyrrolinyl))ethyl] acetamides (LPK-26). LPK-26 showed a high affinity to K-opioid receptor with the K-i value of 0.64 nM and,the low affinities to g-opioid receptor and delta-opioid receptor with the K-i values of 1170 nM and > 10,000 nM, respectively. It stimulated [S-35] GTP gamma S 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 K-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. (c) 2008 Elsevier B.V All rights reserved.