Oleynek J J, Sedlock D M, Barrow C J, Appell K C, Casiano F, Haycock D, Ward S J, Kaplita P, Gillum A M
Department of Natural Products Biology, Sterling Winthrop Pharmaceuticals, Collegeville, PA 19426-0900.
J Antibiot (Tokyo). 1994 Apr;47(4):399-410. doi: 10.7164/antibiotics.47.399.
WIN 64821, a secondary metabolite produced by Aspergillus sp. (ATCC 74177) was found to inhibit radiolabeled substance P (SP) binding in a variety of tissues, including those of human origin. This compound inhibited, in a competitive manner, the binding of SP with Ki values ranging from 0.24 microM in human astrocytoma U-373 MG cells to 7.89 microM in rat submaxillary membranes. Additionally, WIN 64821 was found to inhibit 125I-NKA binding to the NK2 receptor in human tissue at a concentration equivalent to its NK1 activity (0.26 microM). The inhibitory activity of WIN 64821 against an NK3 selective ligand, 3H-senktide, was found to be much weaker (Ki = 15.2 microM). WIN 64821 was also evaluated in NK1 functional assays and was found to be a competitive antagonist of SP-induced contractility in the guinea pig ileum (pA2 = 6.6) as well as an inhibitor of SP-induced 45Ca2+ efflux from human astrocytoma U-373 MG cells (IC50 = 0.6 microM). In a rat vas deferens model, WIN 64821 inhibited eledoisin-induced contractility with an IC50 of 3.4 microM indicating functional antagonism at the NK2 receptor. The data presented in this study provide biochemical, pharmacological and functional evidence supporting WIN 64821 as a competitive neurokinin antagonist.
WIN 64821是由曲霉属（ATCC 74177）产生的一种次级代谢产物，被发现可抑制多种组织（包括人类来源的组织）中放射性标记的P物质（SP）的结合。该化合物以竞争性方式抑制SP的结合，其Ki值范围从人星形细胞瘤U-373 MG细胞中的0.24微摩尔到大鼠下颌下膜中的7.89微摩尔。此外，发现WIN 64821在相当于其NK1活性（0.26微摩尔）的浓度下可抑制人组织中125I-NKA与NK2受体的结合。WIN 64821对NK3选择性配体3H-速激肽的抑制活性要弱得多（Ki = 15.2微摩尔）。还在NK1功能测定中评估了WIN 64821，发现它是豚鼠回肠中SP诱导的收缩的竞争性拮抗剂（pA2 = 6.6），也是人星形细胞瘤U-373 MG细胞中SP诱导的45Ca2+外流的抑制剂（IC50 = 0.6微摩尔）。在大鼠输精管模型中，WIN 64821以3.4微摩尔的IC50抑制eledoisin诱导的收缩，表明在NK2受体处具有功能拮抗作用。本研究中提供的数据提供了生化、药理和功能证据，支持WIN 64821作为竞争性神经激肽拮抗剂。
