α-亚甲基-γ-丁内酯类GPR52拮抗剂的设计与合成研究

Design and Synthesis Studies ofα-Methylene-γ-butyrolactones Antagonists of GPR52

GPR52是一种孤儿G蛋白偶联受体,在纹状体中高度表达,与神经退行性疾病亨廷顿舞蹈症(HD)的发生相关.变异亨廷顿蛋白(mHTT)的蓄积是亨廷顿舞蹈症的主要发病原因.通过拮抗GPR52活性降低m HTT的水平是一种有潜力的新型治疗手段.通过高通量筛选,发现天然产物E7作为共价拮抗剂对GPR52具有一定的抑制作用(IC_(50)=12.0μmol/L).本工作通过保留关键母核α-亚甲基-γ-丁内酯,对E7进行结构简化并改造,设计合成了34个新型α-亚甲基-γ-丁内酯衍生物,其中(±)-4-甲氧基苯甲酸-[(2S,3R)-4-甲亚基-5-氧亚基-2-(噻吩-2-基)四氢呋喃-3-基]甲基酯(10m)对GPR52具有较好的拮抗活性(IC_(50)=0.58μmol/L).同时,初步确定了此类新型GPR52拮抗剂的构效关系,并验证了α-亚甲基-γ-丁内酯母核的必要性.

GPR52 is an orphan G protein-coupled receptor,which is highly expressed in the striatum and associated with Huntingdon’s disease(HD),a neurodegenerative disease.HD is caused by the accumulation of mutant Huntingdon’s protein(mHTT).Reduction of mHTT level by inhibition of GPR52 is a novel potential method of HD therapy.Through high throughput screening,the natural product E7 was found as a covalent antagonist against GPR52(IC_(50)=12.0μmol/L).In this study,the structure of E7 was simplified and theα-methylene-γ-butyrolactone moiety was retained.And 34 novelα-methylene-γ-butyrolactone derivatives were designed and synthesized,of which(±)-((2S,3R)-4-methylene-5-oxo-2-(thiophen-2-yl)-tetrahydrofuran-3-yl)methyl 4-methoxybenzoate(10m)showed most potent antagonistic activity against GPR52(IC_(50)=0.58μmol/L).Meanwhile,the structure-activity relationship was determined preliminarily and the necessary ofα-methylene-γ-butyrolactone moiety was verified.