Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy.
Department of Drug and Health Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Molecules. 2023 Jun 17;28(12):4827. doi: 10.3390/molecules28124827.
In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. To do that, the phenyl ring in the -substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (-)---normetazocine skeleton. In radioligand binding assays, compounds and were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (K = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound showed an antagonist effect against DAMGO ([D-Ala, N-MePhe, Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound produced naloxone reversible effect at MOR. Moreover, compound , as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall-Selitto test.
在这项工作中，我们报告了 LP1 类似物的体外和体内药理学特性，以完成旨在生成具有改善镇痛作用的化合物的一系列结构修饰。为此，我们将先导化合物 LP1 的 -取代基中的苯环替换为富电子或缺电子环，并通过丙酰胺或丁酰胺间隔基连接到 (-)---去甲左啡诺骨架的碱性氮上。在放射性配体结合测定中，化合物 和 被发现对 μ 阿片受体 (MOR) 具有纳摩尔结合亲和力（K = 5.96 ± 0.08 nM 和 1.49 ± 0.24 nM，分别）。在小鼠输精管 (MVD) 测定中，化合物 对 DAMGO ([D-Ala, N-MePhe, Gly-ol]-enkephalin)，一种高度选择性的 MOR 原型激动剂，表现出拮抗剂作用，而化合物 对 MOR 产生纳洛酮可逆转作用。此外，化合物 ，与 LP1 和 DAMGO 一样，在 MOR 中具有很强的活性，能够通过小鼠尾巴闪烁试验和大鼠足压阈值 (PPT) 来减轻热痛和炎症痛。
