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 isolated tissue assays. UP 269-6 bound selectively to AT(1) receptors as evidenced by the inhibition of specific [I-125] Sar(1), Ile(8)-AII binding in rat adrenal membranes (IC50=35.8 nM) and in cultured vascular smooth muscle cells (IC50=23.8 nM). UP 269-6 displayed a very high selectivity 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 rabbit aortic strips. The pattern of AII antagonism suggested competitive 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 10(-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 potent 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 affect the contractile response to KCl or phenylephrine in rabbit aorta and exhibited no effect on angiotensin converting enzyme activity. These data demonstrate that UP 269-6 is a highly potent, selective and specific AT(1) receptor antagonist.