WIN 64821, A NEW COMPETITIVE ANTAGONIST TO SUBSTANCE-P, ISOLATED FROM AN ASPERGILLUS SPECIES - STRUCTURE DETERMINATION AND SOLUTION CONFORMATION
WIN 64821, A NEW COMPETITIVE ANTAGONIST TO SUBSTANCE-P, ISOLATED FROM AN ASPERGILLUS SPECIES - STRUCTURE DETERMINATION AND SOLUTION CONFORMATION
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DOI：
10.1021/jo00074a031
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发表时间：
1993-10-22
影响因子：
3.6
通讯作者：
COOPER, R
中科院分区：
文献类型：
--
作者：
BARROW, CJ;CAI, P;COOPER, R
从最初从土壤中分离的曲霉培养物中分离出两种新的二酮哌嗪二聚体，WIN 64821（1a）和WIN 64745（2），并根据化学和光谱证据确定了它们的结构。二聚体1a具有C1对称性，具有由一个苯丙氨酸和一个色氨酸残基生物合成构建的两个等效单体亚基中的每一个。二聚体1a是人NK 1受体处P物质（SP）的竞争性拮抗剂，在人星形细胞瘤细胞中对[I-125]SP的抑制剂亲和力常数（K（i））为230 +/- 30 nM。通过NMR数据分析和分子模拟确定了la和不对称甲基化衍生物1b的溶液结构。溶液的结构，连同一些结构-活性数据，表明这些分子在NK 1受体的可能的结合构象。
Two new diketopiperazine dimers, WIN 64821 (1a) and WIN 64745 (2), were isolated from an Aspergillus culture originally isolated from soil and their structures established on the basis of chemical and spectroscopic evidence. The dimer 1a has C1 symmetry with each of two equivalent monomeric subunits biosynthetically constructed from one phenylalanine and one tryptophan residue. Dimer 1a is a competitive antagonist to substance P (SP) at the human NK1 receptor with an inhibitor affinity constant (K(i)) of 230 +/- 30 nM against [I-125]SP in human astrocytoma cells. The solution structures of la and the nonsymmetrical methylation derivative 1b were determined by analysis of NMR data and molecular modeling. The solution structures, together with some structure-activity data, suggest a probable binding conformation for these molecules at the NK1 receptor.