Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
Bioorg Med Chem. 2018 Oct 1;26(18):5069-5078. doi: 10.1016/j.bmc.2018.09.007. Epub 2018 Sep 6.
CRA13; a peripheral dual CBR/CBR agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CBR agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CBR affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CBR and CBR activity revealed the alcohol metabolite 8c as a more potent and more effective CBR ligand with attenuated CBR affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CBR affinity and reduced CBR affinity. The CBR binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.
CRA13 是一种外周性双重 CBR/CBR 激动剂，具有临床证明的镇痛特性，由于中枢 CBR 激动作用而渗透到中枢神经系统，产生不良反应。通过脂溶性较低、CBR 亲和力降低的化合物可以避免这种不良反应。代谢产生的脂溶性较低的代谢物可能是活性代谢物。一些 CRA13 的氧化代谢物及其类似物被合成作为脂溶性较低的 CRA13 类似物。研究这些化合物的 CBR 和 CBR 活性表明，醇代谢物 8c 作为一种更有效、更有效的 CBR 配体，相对于 CRA13，其 CBR 亲和力降低。此外，醇类似物 8b 和甲酯 12a 具有增强的 CBR 亲和力和降低的 CBR 亲和力。醇类似物 8b 的 CBR 结合亲和力与 CRA13 相似，而甲酯 12a 的结合亲和力更强。计算研究提供了对可能的分子相互作用的深入了解，这些相互作用可能解释了这些化合物所引起的生物学活性的差异。
