Derivatives of salicylic acid (SA) and benzoic acid prevent endothelin-1 (E
T-1) binding to ETA receptors. This study analyzed actions of 30 derivative
s of benzoic acid and salicylic acid on I-125-ET-1 binding to recombinant r
at ETA receptors. The most active compounds were 3,5-dibromosalicylic acid
(Br2SA, K-i = 0.5 mM) and 3,5-diiodosalicylic acid (K-i = 0.3 mM). They wer
e about 50 times more potent than SA and aspirin. Br2SA inhibited equilibri
um I-125-ET-1 binding in an apparently competitive manner. It accelerated 8
-fold the dissociation of I-125-ET-1 receptor complexes and did not modify
the second order rate constant of association of I-125-ET-1 to its receptor
s. Br2SA also decreased the affinity of ETA receptors for receptor antagoni
sts BQ-123 and bosentan. Br2SA accelerated dissociation of I-125-ET-1-solub
ilized ETA receptor complexes and decreased the apparent molecular size of
solubilized receptors. Br2SA and 3,5-diiodosalicylic acid inhibited two cel
lular actions of ET-1: the mobilization of intracellular Ca2+ stores in iso
lated cells and contractions of rat aortic rings. They accelerated the rela
xing action of BQ-123 and bosentan in ET-1-treated aortic rings. The result
s suggest the existence of an allosteric modifier site on ETA receptors tha
t recognizes selected derivatives of SA. SA derivatives might be of therape
utic interest to relieve tight ET-1 binding and to favor actions of recepto
r antagonists.