IN-VITRO PHARMACOLOGICAL CHARACTERIZATION OF UP-269-6, A NOVEL NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST

The in vitro pharmacology of UP 269-6, a novel nonpeptide angiotensin II antagonist, was examined in radioligand binding and functional isol ated tissue assays. UP 269-6 bound selectively to AT(1) receptors as e videnced by the inhibition of specific [I-125] Sar(1), Ile(8)-AII bind ing in rat adrenal membranes (IC50=35.8 nM) and in cultured vascular s mooth muscle cells (IC50=23.8 nM). UP 269-6 displayed a very high sele ctivity for the AT(1) compared to the AT(2) receptor subtype (IC50>10, 000 nM). UP 269-6 inhibited the AII-induced contraction of isolated ra bbit aortic strips. The pattern of AII antagonism suggested competitiv e antagonism at low concentrations (10(-10) 3 x 10(-10), 10(-9) M) of UP 269-6 and insurmountable antagonism at higher concentrations (3 x 1 0(-9), 10(-8), 3 x 10(-8) M). Based on the calculated pA(2) values, UP 269-6 (9.86+/-0.25) was an angiotensin II receptor antagonist as pote nt as L-158,809 (9.82+/-0.37) and much more potent than losartan (7.96 +/-0.38). UP 269-6 was devoid of affinity (IC50 > 10,000 nM) for many other receptors, ion channels and uptake sites, demonstrating its high specificity for AII receptors. Furthermore, this compound did not aff ect the contractile response to KCl or phenylephrine in rabbit aorta a nd exhibited no effect on angiotensin converting enzyme activity. Thes e data demonstrate that UP 269-6 is a highly potent, selective and spe cific AT(1) receptor antagonist.