NOVEL NEUROKININ ANTAGONIST PRODUCED BY ANAspergillus sp . II . BIOLOGICAL ACTIVITY

WIN64821, 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 fiu in human astrocytoma U-373 MGcells to 7.89 /xm in rat submaxillary membranes. Additionally, WIN64821 was found to inhibit 125I-NKA binding to the NK2receptor in human tissue at a concentration equivalent to its NK1 activity (0.26 ^m). The inhibitory activity of WIN64821 against an NK3 selective ligand, 3H-senktide, was found to be much weaker (Aj= 15.2/*m). WIN64821 was also evaluated in NK1functional assays and was found to be a competitive antagonist of SPinduced contractility in the guinea pig ileum (pA2=6.6) as well as an inhibitor of SP-induced 45Ca2 + efflux from human astrocytoma U-373 MGcells (IC50 =0.6 jam). In a rat vas deferens model, WIN 64821 inhibited eledoisin-induced contractility with an IC50 of 3.4^M indicating functional antagonism at the NK2 receptor. The data presented in this study provide biochemical, pharmacological and functional evidence supporting WIN64821 as a competitive neurokinin antagonist.