Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788.

Abstract

We describe the characteristics of a potent and selective endothelin (ET) B-receptor antagonist, BQ-788

In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ETB receptor

“…Similar observations from other laboratories resuited in withdrawal of IRL 1038 [19]. In our assay systems, also the ETB receptor potency (IC~0:48 nM) and selectivity (80-fold) of BQ 788 proved to be less favorable than previously published data describing an IC50 of 1.2 nM on ETB receptors and a more than 1000-fold ETB selectivity for human receptors [17]. Possible explanations for this discrepancy include the use of different assay systems or proteolytic degradation of the compound.…”

“…IRL 1038 [16], BQ 788 [17] and RES 701 [ 8] have been described. Among these antagonists, BQ 788 r ~veals only a low selectivity for ETB on human ET receptors, I RL 1038 lacks chemical stability [19] and the synthetic form f RES 701 is much less potent than the naturally occurring I eptide [20].…”

Regulation of Guinea pig intestinal peristalsis by endogenous endothelin acting at ETB receptors

“…21 At a concentration of 3 µmol/L, which previously has been shown to be effective and selective for ET A receptors, 14,16,20 BQ-123 abolished the stimulant influence of ET-1 on propulsive motility and unmasked an inhibitory ET-1 action that was indistinguishable from that of the ET B receptor agonist STX-6c. It thus seems that, after exposure to ET-1 under normal conditions, the ET A receptor-mediated stimulation of peristalsis overrides the ET B receptor-mediated inhibition of peristalsis.…”

“…The inhibitory action of STX-6c on propulsive motility, on the other hand, was prevented by BQ-788, which at 3 µmol/L is an effective and selective ET B receptor antagonist. 16,21,28 The inability of BQ-788 to uncover a properistaltic effect of STX-6c attests to the selective action of this snake venom peptide at ET B receptors. As was noted in other functional tests, 10,[13][14][15][16]28 the peristaltic motor effect of ET A receptor activation tended to be attenuated by BQ-788 and that of ET B receptor activation diminished by BQ-123.…”

“…21 The third goal was to elucidate the sites of ET action, although the complexity of the neural control and muscular effector systems of propulsive motility limits this kind of analysis. The fourth objective was to seek pharmacologic evidence for an involvement of endogenous ETs in peristaltic motor regulation.…”