EXP063, A NONPEPTIDE ANGIOTENSIN-II AND BETA-ADRENERGIC-RECEPTOR ANTAGONIST

EXP063 l-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid} was de signed to possess both the angiotensin II (Ang II) and beta adrenergic receptor antagonistic properties. EXP063 inhibited the specific bindi ng of [I-125]Sar1,lle8-Ang II in rat adrenal membranes with K(i) value s of 3.9 +/- 0.6 nM for the Ang II type 1 and > 1 muM for the Ang II t ype 2 receptor binding sites. It displaced [H-3]dihydroalprenolol in t he rat cerebral frontal cortex with a K(i) of 80 +/- 13 nM. EXP063 ant agonized the contractile effect of Ang II competitively (pA2 = 8.9 +/- 0.1) and selectively in rabbit aorta and guinea pig ileum. EXP063 app ears to be a partial beta adrenoceptor agonist as it increased heart r ate in vitro and in vivo. At 1 and 1 0 muM, it inhibited the positive inotropic effect of isoproterenol in guinea pig atria. In pithed rats, EXP063 was more potent in blocking the pressor effect of Ang II than the positive chronotropic effect of isoproterenol. In renal hypertensi ve rats, EXP063 given i.v. produced a long-lasting decrease in blood p ressure for at least 6 hr with an ED30 of 0.53 mg/kg. In summary, this study demonstrates that EXP063 is a novel chemical entity possessing both the Ang II and beta adrenergic receptor blocking properties and, thus, represents a promising agent for the treatment of hypertension a nd congestive heart failure.