The pharmacologic profile of 606A, a novel angiotensin II receptor antagonist

The pharmacologic profile of a novel angiotensin I (AT 1 ) receptor antagonist 606A was studied in various in vitro and in vivo preparations. The 606A showed a high affinity to AT 1 receptors [inhibition constant (K i ), 12.8 ± 0.4 nM] in rabbit adrenal cortical membrane and a low affinity to AT 2 receptors (K i , > 1 mM) in bovine cerebellar membrane, indicating potent and selective AT 1 properties. In the guinea pig aorta, 606A reduced the maximal angiotensin II-induced contraction (pD' 2 , 9.06 ± 0.04), whereas EXP3174 showed suppression of the maximum response and a shift to the right of the concentration-response curve at lower and higher concentrations, respectively (conventionally calculated pD' 2 , 8.61 ± 0.23). The 606A had no effects on KC1-, norepinephrine-, serotonin-, and endothelin-1-induced contractions or any agonist activities. In anesthetized dogs, 606A inhibited the angiotensin II-induced pressor response 35 times more potently than losartan. In renal hypertensive rats and spontaneously hypertensive rats (SHRs), 606A decreased systolic blood pressure 10 and 3 times more potently than losartan, respectively, without any chronotropic effects. By repeated administration of 606A to SHRs for 2 weeks, an augmentation of the hypotensive effect was observed. No rebound phenomena occurred after discontinuation. These results indicate that 606A is a potent AT 1 -selective insurmountable angiotensin II receptor antagonist having more potent angiotensin II receptor antagonistic and hypotensive effects than losartan in in vivo models. 606A is suggested to be a useful agent for the treatment of patients with hypertension.