Department of Medicinal Chemistry , Virginia Commonwealth University , 800 E. Leigh Street , Richmond , Virginia 23298 , United States.
Department of Pharmacology and Toxicology , Virginia Commonwealth University , 1112 East Clay Street , Richmond , Virginia 23298 , United States.
J Med Chem. 2019 Jan 24;62(2):561-574. doi: 10.1021/acs.jmedchem.8b01158. Epub 2019 Jan 11.
μ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addiction. On the basis of previous work in our laboratory, NAP, a 6β- N-4'-pyridyl substituted naltrexamine derivative, was identified as a peripheral MOR antagonist that may be used to treat OIC. To further explore its structure-activity relationship, a new series of NAP derivatives were designed, synthesized, and biologically evaluated. Among these derivatives, NFP and NYP significantly antagonized the antinociception effect of morphine. Whereas NAP acted mainly peripherally, its derivatives NFP and NYP actually can act centrally. Furthermore, NFP produced significantly lesser withdrawal symptoms than naloxone at similar doses. These results suggest that NFP has the potential to be a lead compound to treat opioid abuse and addiction.
μ 阿片受体（MOR）激动剂已被广泛应用于治疗中重度疼痛。然而，它们的应用伴随着许多不良反应，包括阿片类药物引起的便秘（OIC）、呼吸抑制和成瘾。基于我们实验室之前的工作，NAP，一种 6β-N-4′-吡啶取代的纳曲胺衍生物，被鉴定为一种外周 MOR 拮抗剂，可用于治疗 OIC。为了进一步探索其构效关系，设计、合成并生物评价了一系列新的 NAP 衍生物。在这些衍生物中，NFP 和 NYP 显著拮抗了吗啡的镇痛作用。虽然 NAP 主要作用于外周，但它的衍生物 NFP 和 NYP 实际上可以作用于中枢。此外，NFP 在相似剂量下产生的戒断症状明显少于纳洛酮。这些结果表明，NFP 有可能成为治疗阿片类药物滥用和成瘾的先导化合物。
