ENDOTHELIN ANALOGS WHICH DISTINGUISH VASOCONSTRICTOR AND VASODILATOR ET(B) RECEPTORS

[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 vasoconstric tor ET(B) agonist, and a non-competitive vasodilator ET(B) antagonist with no agonist activity. BMS-184697 was a potent ET(A) antagonist, a potent vasoconstrictor ET(B) agonist, and a vasodilator ET(B) agonist with moderate potency. The ability of BMS-184696 to activate the vasoc onstrictor ET(B) receptor but not the vasodilator ET(B) receptor, desp ite 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.