Janecka Anna, Staniszewska Renata, Fichna Jakub
Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, Medical University, Lodz, Poland.
Curr Med Chem. 2007;14(30):3201-8. doi: 10.2174/092986707782793880.
Opiate alkaloids, such as morphine, are powerful analgesic agents that are the drugs of choice for the treatment of severe pain. The pharmacological effects of opiates are mediated through the binding and activation of membrane-bound opioid receptors that are found in the central and peripheral nervous systems. Opioid receptors have been classified into three different types, mu, delta and kappa, and are activated by the specific ligands. It has been demonstrated that the most potent antinociceptive effects are mediated by the mu-receptor. However, until 1997 no endogenous ligand for this receptor was known. The identification of endomorphins opened a new era in the research of the mu-opioid system. They are the first reported brain peptides that label mu-receptor with high affinity and selectivity and therefore are proposed as the endogenous mu-opioid receptor ligands. Morphine and endomorphins act as agonists at the same mu-opioid receptor, but the latter are thought to inhibit pain without some of the undesired side-effects of plant opiates. This observation encouraged extensive studies on the possible use of endomorphin analogs as analgesics instead of morphine. This review summarizes a decade of research on structure-activity relationship studies of endomorphin analogs, aimed at obtaining compounds with increased bioavailability, in particular with better barrier penetration and resistance against enzymatic degradation. Chemical modifications that led to obtaining potent and selective agonists and antagonists based on the structure of endomorphins are discussed.
阿片生物碱，如吗啡，是强效镇痛剂，是治疗重度疼痛的首选药物。阿片类药物的药理作用是通过与中枢和外周神经系统中发现的膜结合阿片受体结合并激活来介导的。阿片受体已被分为三种不同类型，即μ、δ和κ，它们由特定配体激活。已证明最有效的抗伤害感受作用是由μ受体介导的。然而，直到1997年，该受体的内源性配体还不为人所知。内吗啡肽的发现开启了μ阿片系统研究的新时代。它们是首次报道的能以高亲和力和选择性标记μ受体的脑肽，因此被认为是内源性μ阿片受体配体。吗啡和内吗啡肽在同一μ阿片受体上作为激动剂起作用，但后者被认为在抑制疼痛时没有植物阿片类药物的一些不良副作用。这一观察结果促使人们对使用内吗啡肽类似物替代吗啡作为镇痛药的可能性进行了广泛研究。这篇综述总结了对内吗啡肽类似物构效关系研究的十年，旨在获得生物利用度更高的化合物，特别是具有更好的屏障穿透性和抗酶降解能力的化合物。文中讨论了基于内吗啡肽结构获得强效和选择性激动剂及拮抗剂的化学修饰。
