Abstract
Fractionation of an extract of Phyllanthus niruri, based on its ability to inhibit [ 125 I]-ET-1 binding to A10 cells (rat thoracic aortic smooth muscle cells), led to the isolation of three non-peptidic endothelin-1 (ET-1) antagonists, which have been identified as the lignans phyllanthin [1], hypophyllanthin [2], and nirtetralin [3]. These isolates were also found to inhibit [ 125 I]-ET-1 binding to the recombinant human ET A receptor expressed in Chinese hamster ovary cells (CHO-ET A ), but were inactive against the recombinant ET B receptor. The most potent compound was 2 with an IC 50 value of 40 μM. By means of a microphysiometer, 2 was found to attenuate ET-1-induced acceleration in the rate of acid extrusion from CHO-ET A consistent with ET-1 antagonistic activity. Screening of synthetic 1 -phenyl-tetrahydronaphthalene-derived analogues revealed that 5,8-dimethoxy-6-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (BL-4170, 4) also inhibited [ 125 I]-ET-1 binding.
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