Lattmann E, Sattayasai J, Narayanan R, Ngoc N, Burrell D, Balaram P N, Palizdar T, Lattmann P
School of Life and Health Sciences , Aston University , Aston Triangle , Birmingham B4 7ET , England , UK . Email:
Department of Pharmacology , Faculty of Medicine , Khon Kaen University , 40002 Khon Kaen , Thailand.
Medchemcomm. 2017 Feb 17;8(3):680-685. doi: 10.1039/c6md00707d. eCollection 2017 Mar 1.
Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium)-induced inflammation was analysed for derivative and PNB-001 with L-365,260 as a standard. The IC of PNB-001 was determined to be 10 nM. Subsequent evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay, in which the analgesic effect of 1.5 mg kg PNB-001 was equivalent to 40 mg kg tramadol. The CCK-selective antagonist PNB-001 protected rats against indomethacin-induced ulceration at similar doses. The GI protection activity was found to be more potent than that of the 10 mg kg dose of prednisolone, which served as a standard.
芳基化的5-羟基吡咯-2-酮由粘氯酸经两步合成制得，并使用放射性标记结合试验优化为CCK选择性配体。在离体组织制备中证实了这些配体具有CCK拮抗作用。以L-365,260为标准，分析了衍生物和PNB-001对葡聚糖硫酸钠（DSS）诱导的炎症的影响。测定PNB-001的IC为10 nM。随后的评估证实了其在炎症性肠病试验中的抗炎活性。最佳分子PNB-001在福尔马林试验和热板试验中显示出镇痛活性，其中1.5 mg/kg PNB-001的镇痛效果相当于40 mg/kg曲马多。CCK选择性拮抗剂PNB-001在相似剂量下可保护大鼠免受吲哚美辛诱导的溃疡。发现其胃肠道保护活性比作为标准的10 mg/kg剂量的泼尼松龙更强。
