Endothelin analogs which distinguish vasoconstrictor and vasodilator ET B receptors

Abstract

[Pen 1,11, Nle 7, Glu 9, Ala 18]-Sarafotoxin S6b (BMS-184696) and [Pen 1,11, Nle 7, Glu 9, Leu 18]-sarafotoxin S6b (BMS-184697) were synthesized with the aim of preparing ET B receptor antagonists. BMS-184696 was a potent ET a antagonist, an extremely potent vasoconstrictor ET B agonist and a non-competitive vasodilator ET B antagonist with no agonist activity. BMS-184697 was a potent ETA antagonist, a potent vasoconstrictor ET B agonist and a vasodilator ET B agonist with moderate potency. The ability of BMS-184696 to activate the vasoconstrictor ET B receptor but not the vasodilator ET B receptor, despite having high affinity binding to the vasodilator ET B receptor as evidenced by its antagonist activity, strongly suggests the existence of ET B receptor subtypes.