A NOVEL CLASS OF NONPEPTIDIC ENDOTHELIN ANTAGONISTS ISOLATED FROM THEMEDICINAL HERB PHYLLANTHUS-NIRURI

Fractionation of an extract of Phyllanthus niruri, based on its abilit y to inhibit [I-125]-ET-1 binding to A10 cells (rat thoracic aortic sm ooth muscle cells), led to the isolation of three non-peptidic endothe lin-1 (ET-1) antagonists, which have been identified as the lignans ph yllanthin [1], hypophyllanthin [2], and nirtetralin [3]. These isolate d were also found to inhibit [I-125]-ET-1 binding to the recombinant h uman 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 and IC50 value of 40 mu M. By means of a m icrophysiometer, 2 was found to attenuate ET-1-induced acceleration in the rate of acid extrusion from CHO-ET(A) consistent with ET-1 antago nistic activity. Screening of synthetic 1-phenyl-tetrahydronaphthalene -derived analogues revealed that -phenyl-1,2,3,4-tetrahydronaphthalene -2-carboxylic acid (BL-4170, 4) also inhibited [I-125]-ET-1 binding.