Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
Área de Farmacología, Nutrición y Bromatología, Unidad Asociada al IQM y al CIAL (CSIC), Departamento de C.C. Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922 Alcorcón, Spain.
Bioorg Med Chem. 2020 Oct 1;28(19):115672. doi: 10.1016/j.bmc.2020.115672. Epub 2020 Jul 29.
Synthesis and pharmacological evaluation of a new series of cannabinoid receptor antagonists of indazole ether derivatives have been performed. Pharmacological evaluation includes radioligand binding assays with [H]-CP55940 for CB1 and CB2 receptors and functional activity for cannabinoid receptors on isolated tissue. In addition, functional activity of the two synthetic cannabinoids antagonists 18 (PGN36) and 17 (PGN38) were carried out in the osteoblastic cell line MC3T3-E1 that is able to express CB2R upon osteogenic conditions. Both antagonists abolished the increase in collagen type I gene expression by the well-known inducer of bone activity, the HU308 agonist. The results of pharmacological tests have revealed that four of these derivatives behave as CB2R cannabinoid antagonists. In particular, the compounds 17 (PGN38) and 18 (PGN36) highlight as promising candidates as pharmacological tools.
已经合成了一系列新型的大麻素受体拮抗剂吲哚醚衍生物，并对其进行了药理学评价。药理学评价包括用 [H]-CP55940 进行 CB1 和 CB2 受体的放射性配体结合测定，以及对分离组织中大麻素受体的功能活性测定。此外，在能够在成骨条件下表达 CB2R 的成骨细胞系 MC3T3-E1 中，对两种合成大麻素拮抗剂 18（PGN36）和 17（PGN38）的功能活性进行了研究。这两种拮抗剂均能消除已知的骨活性诱导剂 HU308 激动剂引起的Ⅰ型胶原基因表达增加。药理试验结果表明，其中 4 种衍生物表现为 CB2R 大麻素拮抗剂。特别是化合物 17（PGN38）和 18（PGN36）作为有前途的药理学工具候选物。
