WIN-64821, A NOVEL NEUROKININ ANTAGONIST PRODUCED BY AN ASPERGILLUS SP .2. BIOLOGICAL-ACTIVITY

WIN 64821, a secondary metabolite produced by Aspergillus sp. (ATCC 74 177) was found to inhibit radiolabeled substance P (SP) binding in a v ariety of tissues, including those of human origin. This compound inhi bited, in a competitive manner, the binding of SP with Ki values rangi ng from 0.24 mu M in human astrocytoma U-373 MG cells to 7.89 mu M in rat submaxillary membranes. Additionally, WIN 64821 was found to inhib it I-125-NKA binding to the NK2 receptor in human tissue at a concentr ation equivalent to its NK1 activity (0.26 mu M). The inhibitory activ ity of WIN 64821 against an NK3 selective ligand, H-3-senktide, was fo und to be much weaker (Ki=15.2 mu M). 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 (pA(2)=6.6) as well a s an inhibitor of SP-induced Ca-45(2+) efflux from human astrocytoma U -373 MG cells (IC50 =0.6 mu M). In a rat vas deferens model, WIN 64821 inhibited eledoisin-induced contractility with an IC50 of 3.4 mu M in dicating functional antagonism at the NK2 receptor. The data presented in this study provide biochemical, pharmacological and functional evi dence supporting WIN 64821 as a competitive neurokinin antagonist.