Endothelin analogs which distinguish vasoconstrictor and vasodilator ETB receptors.
[Pen 1,11, Nle7, Glu9, Ala18]-Sarafotoxin S6b (BMS-184696) and [Pen1,11, Nle7, Glu9, Leu18]-sarafotoxin S6b (BMS-184697) were synthesized with the aim of preparing ETB receptor antagonists. BMS-184696 was a potent ETA antagonist, an extremely potent vasoconstrictor ETB agonist, and a non-competitive vasodilator ETB antagonist with no agonist activity. BMS-184697 was a potent ETA antagonist, a potent vasoconstrictor ETB agonist, and a vasodilator ETB agonist with moderate potency. The ability of BMS-184696 to activate the vasoconstrictor ETB receptor but not the vasodilator ETB receptor, despite having high affinity binding to the vasodilator ETB receptor as evidenced by its antagonist activity, strongly suggests the existence of ETB receptor subtypes.
Natarajan
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S
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Hunt
J T
JT
Festin
S
S
Serafino
R
R
Zhang
R
R
Moreland
S
S
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D066298:In Vitro Techniques; D010455:Peptides / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
C097273:BMS 184696; C097274:BMS 184697; D065128:Endothelin Receptor Antagonists; D010455:Peptides; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin