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Methylation Products of 6β- N-Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-07-23 , DOI: 10.1021/acschemneuro.8b00234 Yi Zheng 1 , Samuel Obeng 1 , Huiqun Wang 1 , David L Stevens 2 , Essie Komla 2 , Dana E Selley 2 , William L Dewey 2 , Hamid I Akbarali 2 , Yan Zhang 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-07-23 , DOI: 10.1021/acschemneuro.8b00234 Yi Zheng 1 , Samuel Obeng 1 , Huiqun Wang 1 , David L Stevens 2 , Essie Komla 2 , Dana E Selley 2 , William L Dewey 2 , Hamid I Akbarali 2 , Yan Zhang 1
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Two 6β- N-heterocyclic naltrexamine derivatives, NAP and NMP, have been identified as peripherally selective mu opioid receptor (MOR) antagonists. To further enhance the peripheral selectivity of both compounds, the 17-amino group and the nitrogen atom of the pyridine ring in both NAP and NMP were methylated to obtain dMNAP and dMNMP, respectively. Compared with NAP and NMP, the binding affinities of dMNAP and dMNMP shifted to MOR and KOR (kappa opioid receptor) dual selective and they acted as moderate efficacy partial agonists. The results from radioligand binding studies were further confirmed by molecular docking studies. In vivo studies demonstrated that dMNAP and dMNMP did not produce antinociception nor did they antagonize morphine's antinociceptive activity, indicating that these compounds did not act on the central nervous system. Meanwhile, both dMNAP and dMNMP significantly slowed down fecal excretion, which indicated that they were peripherally acting opioid receptor agonists. All together, these results suggested that dMNAP and dMNMP acted as peripheral mu/kappa opioid receptor modulators and may be applicable in the treatment of diarrhea in patients with bowel dysfunction.
中文翻译：
6β-N-杂环取代的纳曲胺衍生物作为潜在的外周阿片受体调节剂的甲基化产物。
已经确定了两种6β-N-杂环纳曲胺衍生物NAP和NMP作为外周选择性μ阿片受体（MOR）拮抗剂。为了进一步提高这两种化合物的外围选择性，将NAP和NMP中吡啶环的17-氨基和氮原子甲基化，分别得到dMNAP和dMNMP。与NAP和NMP相比，dMNAP和dMNMP的结合亲和力转向了MOR和KOR（κ阿片受体）双重选择性，它们充当了中等效力的部分激动剂。通过分子对接研究进一步证实了放射性配体结合研究的结果。体内研究表明，dMNAP和dMNMP不会产生抗伤害感受，也不会拮抗吗啡的抗伤害感受活性，表明这些化合物没有作用于中枢神经系统。同时，dMNAP和dMNMP均显着减慢了粪便的排泄，这表明它们是外周作用的阿片样物质受体激动剂。总之，这些结果表明，dMNAP和dMNMP充当外周mu /κ阿片样物质受体调节剂，并且可能适用于肠功能障碍患者的腹泻治疗。
更新日期：2018-07-12
中文翻译：
6β-N-杂环取代的纳曲胺衍生物作为潜在的外周阿片受体调节剂的甲基化产物。
已经确定了两种6β-N-杂环纳曲胺衍生物NAP和NMP作为外周选择性μ阿片受体（MOR）拮抗剂。为了进一步提高这两种化合物的外围选择性，将NAP和NMP中吡啶环的17-氨基和氮原子甲基化，分别得到dMNAP和dMNMP。与NAP和NMP相比，dMNAP和dMNMP的结合亲和力转向了MOR和KOR（κ阿片受体）双重选择性，它们充当了中等效力的部分激动剂。通过分子对接研究进一步证实了放射性配体结合研究的结果。体内研究表明，dMNAP和dMNMP不会产生抗伤害感受，也不会拮抗吗啡的抗伤害感受活性，表明这些化合物没有作用于中枢神经系统。同时，dMNAP和dMNMP均显着减慢了粪便的排泄，这表明它们是外周作用的阿片样物质受体激动剂。总之，这些结果表明，dMNAP和dMNMP充当外周mu /κ阿片样物质受体调节剂，并且可能适用于肠功能障碍患者的腹泻治疗。
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