THE SELECTIVE ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST LR-B 081 POTENTLYINHIBITS DRINKING INDUCED BY CENTRAL INJECTION OF ANGIOTENSIN-II IN RATS/

LR-B/081, oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl] methyl]-1 (6H)-pyrimidinyl] methyl]-3-thiophenecarboxylate, is a recently develo ped nonpeptide antagonist selective for angiotensin AT(1) receptors. T he drug has been reported to be an insurmountable angiotensin AT(1) re ceptor antagonist endowed with long-lasting antihypertensive activity. A large body of evidence indicates that angiotensin AT(1) receptors m ediate the dipsogenic action of angiotensin II in the central nervous system. The present study evaluated the ability of LR-B/081, in compar ison with losartan and with its active metabolite EXP3174, to inhibit drinking induced by central injection of angiotensin II in water-sated rats. LR-B/081, in the dose range of 10-1000 pmol/rat, dose dependent ly inhibited the drinking response to angiotensin II, 10 pmol/rat. The ID50 of LR-B/081 was 25.9 pmol/rat, while that of losartan and EXP317 4 was 357 and 3.9 pmol/rat, respectively. Therefore LR-B/081 was about 7 times less potent than EXP3174, but about 14 times more potent than the parent molecule losartan. LR-B/081 altered neither carbachol-indu ced water intake, nor 15% fat milk intake in rats, suggesting that its effect on angiotensin II-induced drinking is a behaviourally selectiv e effect. These findings show that LR-B/081 potently inhibits central angiotensin AT(1) receptors involved in the control of body fluid home ostasis and suggest that this drug might be an interesting pharmacolog ical tool to further investigate the role of the central renin-angiote nsin system in physiological or pathological conditions.