Lazarus L H, Bryant S D, Attila M, Salvadori S
Laboratory of Environmental Neuroscience, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Environ Health Perspect. 1994 Aug;102(8):648-54. doi: 10.1289/ehp.94102648.
Naturally occurring environmental substances often mimic endogenous substances found in mammals and are capable of interacting with specific proteins, such as receptors, with a high degree of fidelity and selectivity. Narcotic alkaloids and amphibian skin secretions, introduced into human society through close association with plants and animals through folk medicine and religious divination practices, were incorporated into the armamentarium of the early pharmacopoeia. These skin secretions contain a myriad of potent bioactive substances, including alkaloids, biogenic amines, peptides, enzymes, mucus, and toxins (noxious compounds notwithstanding); each class exhibits a broad range of characteristic properties. One specific group of peptides, the opioids, containing the dermorphins (dermal morphinelike substances) and the deltorphins (delta-selective opioids), display remarkable analgesic properties and include an amino acid with the rare (in a mammalian context) D-enantiomer in lieu of the normal L-isomer. Synthesis of numerous stereospecific analogues and conformational analyses of these peptides provided essential insights into the tertiary composition and microenvironment of the receptor "pocket" and the optimal interactions between receptor and ligand that trigger a biological response; new advances in the synthesis and receptor-binding properties of the deltorphins are discussed in detail. These receptor-specific opioid peptides act as more than mimics of endogenous opioids: their high selectivity for either the mu or delta receptor makes them formidable environmentally derived agents in the search for new antagonists for treating opiate addiction and in the treatment of a wide variety of human disorders.
天然存在的环境物质常常模拟哺乳动物体内的内源性物质，并且能够与特定蛋白质（如受体）以高度的保真度和选择性进行相互作用。通过民间医学和宗教占卜实践与动植物密切接触而引入人类社会的麻醉性生物碱和两栖动物皮肤分泌物，被纳入了早期药典的药物库中。这些皮肤分泌物含有大量强效生物活性物质，包括生物碱、生物胺、肽、酶、黏液和毒素（尽管有有害化合物）；每一类都表现出广泛的特性。一类特定的肽，即阿片样物质，包含了皮啡肽（皮肤类吗啡样物质）和强啡肽（δ-选择性阿片样物质），具有显著的镇痛特性，并且包含一种在哺乳动物环境中罕见的D-对映体氨基酸来替代正常的L-异构体。这些肽的众多立体特异性类似物的合成以及构象分析，为受体“口袋”的三级结构和微环境以及触发生物反应的受体与配体之间的最佳相互作用提供了重要见解；强啡肽在合成和受体结合特性方面的新进展将被详细讨论。这些受体特异性阿片样肽不仅仅是内源性阿片样物质的模拟物：它们对μ或δ受体的高选择性使它们成为在寻找治疗阿片成瘾的新拮抗剂以及治疗多种人类疾病方面强大的环境衍生药物。
