In vitro pharmacology of DuP 753.
DuP 753, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt, was characterized in vitro with respect to its affinity and specificity for functional antagonism of angiotensin II (AII) receptors. In rat adrenal cortical microsomes and cultured aortic smooth muscle cells DuP 753 inhibited the specific binding of [125I]AII in a concentration-dependent manner yielding IC50 values of 1.7 and 2.0 x 10(-8) mol/L, respectively. In contrast, DuP 753 had no appreciable affinity for other receptor systems as well as for Ca2+ channels. Functional antagonism was demonstrated by its blockade of AII-induced 45Ca2+ efflux in rat smooth muscle cells. The AII-induced contraction of rabbit aortic strips was competitively antagonized by DuP 753 resulting in a pA2 value of 8.48. Responses induced by other agonists, such as norepinephrine and KCl, were not altered. No partial agonistic effect was noted in any of the in vitro assays. In addition, DuP 753 (10(-5) mol/L) had no effect on rabbit lung converting enzyme or rat/human renin activity. These data demonstrate that DuP 753 is a highly potent and specific AII receptor antagonist. DuP 753 represents a useful experimental tool for dissecting the role of the renin-angiotensin system.
Chiu
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Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880-0400.
McCall
D E
DE
Price
W A
WA
Wong
P C
PC
Carini
D J
DJ
Duncia
J V
JV
Wexler
R R
RR
Yoo
S E
SE
Johnson
A L
AL
Timmermans
P B
PB
D000302:Adrenal Cortex / Q000187:drug effects; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D019808:Losartan; D009928:Organ Specificity; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan