title: The selective angiotensin AT1 receptor antagonist LR-B/081 potently inhibits drinking induced by central injection of angiotensin II in rats.
abstract: LR-B/081, methyl-2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-1(6H)-pyrimidinyl] methyl]-3-thiophenecarboxylate, is a recently developed nonpeptide antagonist selective for angiotensin AT1 receptors. The drug has been reported to be an insurmountable angiotensin AT1 receptor antagonist endowed with long-lasting antihypertensive activity. A large body of evidence indicates that angiotensin AT1 receptors mediate the dipsogenic action of angiotensin II in the central nervous system. The present study evaluated the ability of LR-B/081, in comparison 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 dependently 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 EXP3174 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-induced water intake, nor 15% fat milk intake in rats, suggesting that its effect on angiotensin II-induced drinking is a behaviourally selective effect. These findings show that LR-B/081 potently inhibits central angiotensin AT1 receptors involved in behaviourally selective effect. These findings show that LR-B/081 potently inhibits central angiotensin AT1 receptors involved in the control of body fluid homeostasis and suggest that this drug might be an interesting pharmacological tool to further investigate the role of the central renin-angiotensin system in physiological or pathological conditions.
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects*; D004435:Eating / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D007928:Lethal Dose 50; D019808:Losartan; D008297:Male; D008892:Milk / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; C094835:LR B-081; D011744:Pyrimidinones; D013777:Tetrazoles; D013876:Thiophenes; D000804:Angiotensin II; D002217:Carbachol; C066026:losartan carboxylic acid; D019808:Losartan