Department of Chemistry and Pharmacy, University of Sassari, via F. Muroni 23/A, 07100, Sassari, Italy.
Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Eur J Med Chem. 2017 Feb 15;127:398-412. doi: 10.1016/j.ejmech.2017.01.002. Epub 2017 Jan 4.
In the last few years, cannabinoid type-2 receptor (CBR) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCBR and hCBR. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)-N-(cis-4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (9) displayed high CB-affinity (KCB = 2.0 ± 0.81 nM) and a notable selectivity (KCB/KCB > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CBR inverse agonists in [S]-GTPγS binding assay. ADME predictions of the newly synthesized CBR ligands suggest a favourable pharmacokinetic profile. Docking studies disclosed the specific pattern of interactions of these derivatives. Our results support that pyridazinone-4-carboxamides represent a new promising scaffold for the development of potent and selective CBR ligands.
在过去的几年中，大麻素类型 2 受体 (CBR) 选择性配体已显示出作为几种疾病的新型治疗药物的巨大潜力。为了发现新的选择性大麻素配体，设计并合成了一系列哒嗪酮-4-甲酰胺，并测试了新衍生物对 hCBR 和 hCBR 的亲和力。6-(4-氯-3-甲基苯基）-2-(4-氟苄基）-N-(顺式-4-甲基环己基）-3-氧代-2,3-二氢哒嗪-4-甲酰胺（9）表现出高 CB 亲和力（KCB=2.0±0.81nM）和显著的选择性（KCB/KCB>2000）。此外，9 和其他活性新合成的实体已被证明在[S]-GTPγS 结合测定中表现为 CBR 反向激动剂。新合成的 CBR 配体的 ADME 预测表明其具有良好的药代动力学特性。对接研究揭示了这些衍生物的特定相互作用模式。我们的结果支持哒嗪酮-4-甲酰胺代表了开发有效且选择性 CBR 配体的新有前途的支架。
