Melatonin MT₁ and MT₂ receptor ligands have been vigorously explored for the last 4 decades. Inspection of approximately 80 publications in the field revealed that most melatonergic ligands were structural analogues of melatonin combining three essential features of the parent compound: an aromatic ring bearing a methoxy group and an amide side chain in a relative arrangement similar to that present in melatonin. While several series of MT₂‐selective agents—agonists, antagonists, or partial agonists—were reported, the field was lacking MT₁‐selective agents. Herein, we describe various approaches toward the development of melatonergic ligands, keeping in mind that most of the molecules/pharmacophores obtained were essentially melatonin copies, even though diverse tri‐ or tetra‐cyclic compounds were explored. In addition to lack of structural diversity, only few studies examined the activity of the reported melatonergic ligands in vivo. Moreover, an extensive pharmacological characterization including biopharmaceutical stability, pharmacokinetic properties, specificity toward other major receptors to name a few remained scarce. For example, many of the antagonists described were not stable in vivo, were not selective for the melatonin receptor subtype of interest, and were not fully characterized from a pharmacological standpoint. Indeed, virtual screening of large compound libraries has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists of new chemotypes. Having said this, the melatonergic field is still lacking subtype‐selective melatonin receptor antagonists “active” in vivo, which are critical to our understanding of melatonin and melatonin receptors’ role in basic physiology and disease.

中文翻译：

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褪黑激素受体配体：药物化学观点。

褪黑激素 MT ₁和 MT ₂受体配体在过去 4 年中得到了大力探索。对该领域大约 80 篇出版物的检查表明，大多数褪黑激素配体是褪黑激素的结构类似物，结合了母体化合物的三个基本特征：一个带有甲氧基的芳环和一个酰胺侧链，其相对排列与褪黑激素中存在的相似。虽然报道了几个系列的 MT ₂选择性药物——激动剂、拮抗剂或部分激动剂，但该领域缺乏 MT ₁——选择性药剂。在这里，我们描述了开发褪黑激素配体的各种方法，记住，即使探索了不同的三环或四环化合物，获得的大多数分子/药效团基本上都是褪黑激素的拷贝。除了缺乏结构多样性之外，只有少数研究检查了所报道的体内褪黑激素配体的活性。此外，广泛的药理学表征，包括生物药物稳定性、药代动力学特性、对其他主要受体的特异性等仍然很少。例如，所描述的许多拮抗剂在体内不稳定，对感兴趣的褪黑激素受体亚型没有选择性，并且从药理学角度没有完全表征。的确，大型化合物库的虚拟筛选导致最近发现了有效和选择性的褪黑激素受体激动剂和新化学型的部分激动剂。尽管如此，褪黑激素领域仍然缺乏体内“活性”的亚型选择性褪黑激素受体拮抗剂，这对于我们理解褪黑激素和褪黑激素受体在基础生理学和疾病中的作用至关重要。