LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential.
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.
Tao
Yi-Min
YM
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
Li
Qing-Lin
QL
Zhang
Cong-Fen
CF
Xu
Xue-Jun
XJ
Chen
Jie
J
Ju
Ya-Wen
YW
Chi
Zhi-Qiang
ZQ
Long
Ya-Qiu
YQ
Liu
Jing-Gen
JG
D019342:Acetic Acid; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000517:prevention & control*; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D011485:Protein Binding; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D000701:Analgesics, Opioid; C529714:LPK-26; D009292:Narcotic Antagonists; D011758:Pyrroles; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019342:Acetic Acid