Angiotensin II (AII) is an octapeptide hormone which is a component of the renin-angiotensin system. Angiotensin II mediates a number of physiological responses in several tissues including the constriction of vascular smooth muscle, the synthesis and secretion of aldosterone by the adrenal cortex, and retention of salt and water by the kidney (W. W. Douglas, "Polypeptides--Angiotensin Plasma Kinins, and Others", in The Pharmacological Basis of Therapeutics (A. G. Gilman et al., eds.) MacMillan, New York, 640-643 (1985).
Radioligand binding studies have shown that Angiotensin II receptors exist in at least two subtypes: AT.sub.1 and AT.sub.2 (A. T. Chiu et al., Biochem. Biophys. Res. Commun. 165:196-203 (1989). The AT.sub.1 subtype is coupled to calcium/inositol phosphate metabolism, and is responsible for the major cardiovascular effects of Angiotensin II (A. T. Chiu et al., J. Pharmacol. Exp. Ther. 252:711-718 (1990)); (D. T. Dudley et al., Mol. Pharmacol. 38:370-377 (1990)). Drugs that block the AT.sub.1 receptor therefore show great potential as antihypertensive agents.
A radiotritiated imidazole [.sup.3 H] DuP 753 (A. T. Chiu et al., Biochem. Biophys. Res. Commun., 172:1195-1202 (1990)) has been used to characterize the AT.sub.1 receptor in rat adrenal cortical membranes and other tissues such as rat aortic smooth muscle cells. Discovering other radioligands, especially those with high specific activity, would be highly desirable. Such new radioligands would be useful tools in exploring and further characterizing receptors in the angiotensin system such as those of the AT.sub.1 type. Radioiodinated peptides such as [.sup.125 I ]AII are known (A. T. Chiu et al., Biochem. Biophys. Res. Commun. 165:196-203 (1989)), but not the radioiodinated imidazoles which are the newly discovered non-peptide AII receptor antagonists of the present invention.
Imidazole AII antagonists such as DuP 753 have been disclosed in EPO 0,253,310 (published Jan. 20, 1988) and EPO 0,324,377 (published Jul. 19, 1989). The radioiodinated compounds of the present invention or their use are not disclosed or suggested by any of the above references.
USPTO Backgrounds
USPTO Backgrounds