The pharmacological profile of KR-31081, a nonpeptide AT1 selective angiotensin receptor antagonist, was investigated by receptor binding studies, functional in vitro assays with rabbit aorta. KR-31081 inhibited the specific binding of [ ] CGP 42112A to human recombinant AT2 receptor (IC50: higher than 10 μM for both). The Hill coefficient for the competition curve of KR-31081 against AT1 receptor was not significantly different from unity (0.99). Scatchard analysis showed that KR-31081 interacted with human recombinant AT1 receptor in a competitive manner, as with losartan. In functional studies with rabbit aorta, KR-31081 competitively inhibited the contractile response to angiotensin II (pKB values: 8.66) with 20-70% decrease in the maximum contractile responses, unlike losartan that showed competitive antagonism without any change in the maximum contractile responses to angiotensin II (pA2 values: 7.59). These results suggest that KR-31081 is a highly potent AT1 selective angiotensin II receptor antagonist with a mode of insurmountable antagonism to be developed as the exploratory potential of this compound.
The pharmacological profile of KR-31081, a newly synthesized AT1 receptor antagonist, was evaluated in pithed rats, conscious renal hypertensive rats (RHRs) and conscious furosemide-treated beagle dogs. In pithed rats, KR-31081 (i.v.) induced a non-parallel right shift in the dose-pressor response curve to angiotensin II (ID50: 0.05 mg/kg) with a dose-dependent reduction in the maximum responses; this antagonistic effect was about 40 times more potent than losartan (ID50: 1.74 mg/kg) which showed competitive antagonism. KR-31081 did not alter the responses induced by other agonists such as norepinephrine and vasopressin. In RHRs, orally given KR-31081 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a higher potency to losartan (ED20: 0.30 and 3.36 mg/kg, respectively). In furosemide-treated dogs, orally given KR-31081 produced a dose-dependent and long-lasting (>8h) antihypertensive effect with a rapid onset of action (time to Emax: 1-1.5 h) and 20-fold greater potency than losartan (ED20: 0.41 and 8.13 mg/kg, respectively). These results suggest that KR-31081 is a potent, orally active AT1 receptor antagonist useful for the research and diagnostic tools as an added exploratory potential.
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