WIN 64821, A NOVEL NEUROKININ ANTAGONIST PRODUCED BY AN Aspergillus sp: II. BIOLOGICAL ACTIVITY

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 μM in h...

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Bibliographic Details
Published in:Journal of antibiotics 1994/04/25, Vol.47(4), pp.399-410
Main Authors: OLEYNEK, JOSEPH J., SEDLOCK, DAVID M., BARROW, COLIN J., APPELL, KENNETH C., CASIANO, FRANCES, HAYCOCK, DEAN, WARD, SUSAN J., KAPLITA, PAUL, GILLUM, AMANDA M.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Aspergillus
Aspergillus - metabolism
Astrocytoma - metabolism
Binding, Competitive - drug effects
Biological and medical sciences
Brain - embryology
Brain - metabolism
Calcium - metabolism
Female
General pharmacology
Guinea Pigs
Humans
Ileum - drug effects
Indoles - metabolism
Indoles - pharmacology
Male
Medical sciences
Muscle Contraction - drug effects
Muscle, Smooth - drug effects
Pharmacognosy. Homeopathy. Health food
Pharmacology. Drug treatments
Piperazines - metabolism
Piperazines - pharmacology
Rats
Receptors, Neurokinin-1 - metabolism
Receptors, Neurokinin-2 - metabolism
Receptors, Neurokinin-3 - metabolism
Submandibular Gland - metabolism
Substance P - antagonists & inhibitors
Tumor Cells, Cultured
Urinary Bladder - metabolism
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Summary: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 μM in human astrocytoma U-373 MG cells to 7.89 μM 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 NKl activity (0.26 μM). The inhibitory activity of WIN 64821 against an NK3 selective ligand, 3H-senktide, was found to be much weaker (Ki=15.2μM). 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 muM). In a rat vas deferens model, WIN 64821 inhibited eledoisin-induced contractility with an IC50 of 3.4 μM 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.
ISSN:0021-8820
1881-1469
DOI:10.7164/antibiotics.47.399