Tao Yi-Min, Li Qing-Lin, Zhang Cong-Fen, Xu Xue-Jun, Chen Jie, Ju Ya-Wen, Chi Zhi-Qiang, Long Ya-Qiu, Liu Jing-Gen
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.
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.
吗啡等镇痛药会引起包括成瘾在内的多种副作用，但κ-阿片受体激动剂可产生镇痛作用而无吗啡样副作用。为了开发具有较低滥用潜力的新型强效镇痛药，我们研究了ICI-199441的衍生物（一种(-)U50,488H的类似物，名为(2-(3,4-二氯)-苯基)-N-甲基-N-[(1S)-1-(2-异丙基)-2-(1-(3-吡咯啉基))乙基]乙酰胺（LPK-26））的镇痛和身体依赖性特性。LPK-26对κ-阿片受体具有高亲和力，Ki值为0.64 nM，对μ-阿片受体和δ-阿片受体的亲和力较低，Ki值分别为1170 nM和>10,000 nM。它刺激[(35)S]GTPγS与G蛋白结合，EC50值为0.0094 nM。在体内，LPK-26在镇痛方面比(-)U50,488H和吗啡更有效，在热板和醋酸扭体试验中的ED50值分别为0.049 mg/kg和0.0084 mg/kg。此外，LPK-26未能诱导身体依赖性，但与吗啡同时给药时可抑制小鼠纳洛酮诱发的跳跃。综上所述，我们的结果表明LPK-26是一种新型选择性κ-阿片受体激动剂，具有高效的镇痛作用和低身体依赖性潜力。它可能对开发镇痛药和可用于减少吗啡诱导的身体依赖性的药物具有重要价值。
