The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist.
KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol- 5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT1) receptors in rabbit aorta and human recombinant AT1 receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (AII) with decreased maximal response (pD'2 = 10.1 +/- 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [125I]AII binding to rabbit aortic membranes (AT1 receptors) and [125I][Sar1, Ile8]AII binding to human recombinant AT1 receptors in a concentration-dependent manner with IC50 values of 0.84 +/- 0.08 nM and 1.92 +/- 0.15 nM, respectively, but did not inhibit specific [125I]AII binding to bovine cerebellum membranes (AT2 receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT1 receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT1 selective angiotensin receptor antagonist which exerts a competitive antagonism in the [125I]AII binding assay and insurmountable AT1 receptor antagonism in the functional study.
Hong
K W
KW
Department of Pharmacology, College of Medicine, Pusan National University, Korea.
Kim
C D
CD
Lee
S H
SH
Yoo
S E
SE
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000031:analogs & derivatives / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000502:physiology; D002417:Cattle; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D019808:Losartan / Q000494:pharmacology; D008566:Membranes; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011994:Recombinant Proteins / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D007457:Iodine Radioisotopes; C111727:KR 31080; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011994:Recombinant Proteins; D013777:Tetrazoles; C099368:angiotensin II, iodo-(Sar(1)-Ile(8))-; D000804:Angiotensin II; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan