Manera Clementina, Malfitano Anna Maria, Parkkari Teija, Lucchesi Valentina, Carpi Sara, Fogli Stefano, Bertini Simone, Laezza Chiara, Ligresti Alessia, Saccomanni Giuseppe, Savinainen Juha R, Ciaglia Elena, Pisanti Simona, Gazzerro Patrizia, Di Marzo Vincenzo, Nieri Paola, Macchia Marco, Bifulco Maurizio
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
Eur J Med Chem. 2015 Jun 5;97:10-8. doi: 10.1016/j.ejmech.2015.04.034. Epub 2015 Apr 24.
Several recent studies suggest that selective CB2 receptor agonists may represent a valid pharmacological approach in the treatment of various diseases due to the absence of relevant psychoactive side effect. In this study, we synthesized and tested a series of new quinoline-2(1H)-one- and 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine derivatives characterized by a 4-methylcyclohexylamido substituent in position 3 of the heterocyclic nucleus with high CB2 receptor affinity and selectivity. Two compounds showing the best binding and selectivity profile behaved as a full agonist and a partial agonist at the CB2 receptor and induced a concentration-dependent decrease of cell viability on LNCaP, a prostatic cancer cell line expressing CB2 receptor. Moreover considering that the CB2 receptor is mainly expressed in cells and organs of the immune system, the same compounds were studied for their potential immune-modulatory and anti-inflammatory effects in activated lymphocytes isolated from healthy controls and multiple sclerosis (MS) patients.
最近的几项研究表明，由于缺乏相关的精神活性副作用，选择性CB2受体激动剂可能是治疗各种疾病的一种有效药理学方法。在本研究中，我们合成并测试了一系列新的喹啉-2(1H)-酮和4-羟基-2-氧代-1,2-二氢-1,8-萘啶衍生物，其特征在于杂环核的3位带有4-甲基环己基酰胺取代基，对CB2受体具有高亲和力和选择性。表现出最佳结合和选择性特征的两种化合物在CB2受体上分别表现为完全激动剂和部分激动剂，并在表达CB2受体的前列腺癌细胞系LNCaP上诱导细胞活力呈浓度依赖性下降。此外，鉴于CB2受体主要在免疫系统的细胞和器官中表达，我们研究了相同化合物对从健康对照和多发性硬化症（MS）患者分离的活化淋巴细胞的潜在免疫调节和抗炎作用。
