Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University, Chodzki 4A, 20-093 Lublin, Poland.
Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Molecules. 2022 May 4;27(9):2930. doi: 10.3390/molecules27092930.
The μ-opioid receptors belong to the family of G protein-coupled receptors (GPCRs), and their activation triggers a cascade of intracellular relays with the final effect of analgesia. Classical agonists of this receptor, such as morphine, are the main targets in the treatment of both acute and chronic pain. However, the dangerous side effects, such as respiratory depression or addiction, significantly limit their widespread use. The allosteric centers of the receptors exhibit large structural diversity within particular types and even subtypes. Currently, a considerable interest is aroused by the modulation of μ-opioid receptors. The application of such a technique may result in a reduction in the dose or even discontinuation of classical opiates, thus eliminating the side effects typical of this class of drugs. Our aim is to obtain a series of 1-aryl-5,6(1)dioxo-2,3-dihydroimidazo[1,2-]imidazole derivatives and provide more information about their activity and selectivity on OP3 (MOP, human mu opioid receptor). The study was based on an observation that some carbonyl derivatives of 1-aryl-2-aminoimidazoline cooperate strongly with morphine or DAMGO in sub-threshold doses, producing similar results to those of normal active doses. To elucidate the possible mechanism of such enhancement, we performed a few in vitro functional tests (involving cAMP and β-arrestin recruitment) and a radioligand binding assay on CHO-K1 cells with the expression of the OP3 receptor. One of the compounds had no orthosteric affinity or intrinsic activity, but inhibited the efficiency of DAMGO. These results allow to conclude that this compound is a negative allosteric modulator (NAM) of the human μ-opioid receptor.
μ-阿片受体属于 G 蛋白偶联受体 (GPCR) 家族，其激活触发了一系列细胞内级联反应，最终产生镇痛作用。该受体的经典激动剂，如吗啡，是治疗急性和慢性疼痛的主要靶点。然而，危险的副作用，如呼吸抑制或成瘾，显著限制了它们的广泛应用。受体的变构中心在特定类型甚至亚型内表现出很大的结构多样性。目前，对μ-阿片受体的调制引起了相当大的兴趣。这种技术的应用可能导致减少剂量甚至停止使用经典阿片类药物，从而消除此类药物的典型副作用。我们的目的是获得一系列 1-芳基-5,6(1)二氧代-2,3-二氢咪唑并[1,2-a]咪唑衍生物，并提供有关其对 OP3（MOP，人 μ 阿片受体）的活性和选择性的更多信息。该研究基于以下观察结果：一些 1-芳基-2-氨基咪唑啉的羰基衍生物在亚阈值剂量下与吗啡或 DAMGO 强烈合作，产生与正常有效剂量相似的结果。为了阐明这种增强的可能机制，我们在表达 OP3 受体的 CHO-K1 细胞上进行了一些体外功能测试（涉及 cAMP 和 β-抑制蛋白募集）和放射性配体结合测定。其中一种化合物没有正位亲和力或内在活性，但抑制了 DAMGO 的效率。这些结果表明，该化合物是人类 μ-阿片受体的负变构调节剂 (NAM)。
