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. 2024 Jan 24;29(3):571. doi: 10.3390/molecules29030571.
μ-opioid receptor ligands such as morphine and fentanyl are the most known and potent painkillers. However, the severe side effects seen with their use significantly limit their widespread use. The continuous broadening of knowledge about the properties of the interactions of the MOP receptor (human mu opioid receptor, OP3) with ligands and specific intracellular signaling pathways allows for the designation of new directions of research with respect to compounds with analgesic effects in a mechanism different from classical ligands. Allosteric modulation is an extremely promising line of research. Compounds with modulator properties may provide a safer alternative to the currently used opioids. The aim of our research was to obtain a series of urea derivatives of 1-aryl-2-aminoimidazoline and to determine their activity, mechanism of biological action and selectivity toward the MOP receptor. The obtained compounds were subjected to functional tests (cAMP accumulation and β-arrestin recruitment) in vitro. One of the obtained compounds, when administered alone, did not show any biological activity, while when co-administered with DAMGO, it inhibited β-arrestin recruitment. These results indicate that this compound is a negative allosteric modulator (NAM) of the human MOP receptor.
μ-阿片受体配体，如吗啡和芬太尼，是最知名和最有效的止痛药。然而，它们在使用中出现的严重副作用显著限制了它们的广泛应用。人们对 MOP 受体（人 μ 阿片受体，OP3）与配体和特定细胞内信号通路相互作用的性质的不断深入了解，使得人们可以指定具有与经典配体不同作用机制的具有镇痛作用的化合物的新研究方向。变构调节是一个极具前景的研究领域。具有调节剂特性的化合物可能为目前使用的阿片类药物提供更安全的替代品。我们的研究目的是获得一系列 1-芳基-2-氨基咪唑啉的脲衍生物，并确定它们对 MOP 受体的活性、作用机制和选择性。所获得的化合物在体外进行了功能测试（cAMP 积累和β-arrestin 募集）。其中一种获得的化合物单独给药时没有表现出任何生物活性，而与 DAMGO 共同给药时，它抑制了β-arrestin 的募集。这些结果表明，该化合物是人类 MOP 受体的负变构调节剂（NAM）。
