Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: in vitro studies.
Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627, ABT-546, A-182086 and A-192621, which exhibit difference in selectivity for ET(A) and ET(B) receptors. In this report, we compare the potency and selectivity of these four antagonists in inhibiting (125)I-labelled ET-1 binding to cloned human ET(A) and ET(B) receptors, and in blocking ET-1-induced functional responses (arachidonic acid release and phosphatidylinositol hydrolysis).
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, U.S.A. ruth.r.wuwong@abbott.com
J Ruth
JR
Wu-Wong
Douglas B
DB
Dixon
William J
WJ
Chiou
Brian K
BK
Sorensen
Gang
G
Liu
H-S
HS
Jae
Andrew
A
Tasker
Thomas W
TW
von Geldern
Martin
M
Winn
Terry J
TJ
Opgenorth
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D000077868:Atrasentan; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D007457:Iodine Radioisotopes / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D014665:Vasodilator Agents / Q000494:pharmacology*
C467893:A 182086; C120508:A 192621; C467892:ABT 546; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007457:Iodine Radioisotopes; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014665:Vasodilator Agents; D016718:Arachidonic Acid; D000077868:Atrasentan