The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of delta-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the delta opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective delta opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the delta opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic delta opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

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二芳基甲基哌嗪类的非肽类δ阿片类激动剂和拮抗剂：我们学到了什么？

选择性δ（δ）阿片样物质激动剂SNC 80和BW373U86的发现，在阿片类药物中具有独特的二芳基甲基哌嗪结构，代表了δ-阿片样物质配体领域的重大进展。最近已经进行了广泛的研究以揭示这类配体的结构-活性关系（SAR），从而为δ阿片受体的药理学表征提供了有价值的工具。这篇综述着重于这种独特的配体系列的SAR，并概述了多年来开发和优化的各种化学路线，以使这些配体可以以克为单位进行合成。继续寻找选择性δ阿片样物质激动剂和拮抗剂，以及具有潜在治疗价值的具有混合阿片样物质激动剂特性的拮抗剂。关于二苯基甲基哌嗪衍生物和相关类似物与阿片样物质受体，特别是与δ阿片样物质系统在分子水平上的相互作用的几个问题仍然没有答案。实际上，新型非肽δ阿片样物质配体的开发和药理学表征仍然是研究的活跃领域，因为它可以更好地理解该受体在多种疾病状态和病症中的作用。