The angiotensin AT 1 receptor antagonist irbesartan has near-peptide affinity and potently blocks receptor signaling

Abstract

The angiotensin II type 1 (AT 1) receptor plays a pivotal role in the regulation of blood pressure and electrolyte balance, and is involved in the control of specific ingestive behaviours. Irbesartan (SR 47436/BMS 186295) is a recently developed angiotensin AT 1 receptor antagonist, chemically described as 2-butyl-3-([2′-{1 H-tetrazol-5-yl}biphenyl-4-yl]methyl)-1,3-diazaspiro (4,4)non-1-en-4-one. Irbesartan displays higher affinity for its target receptor than other similar antagonists. In radioligand binding assays performed on membranes from WB-Fischer 344 (WB) rat liver epithelial cells, irbesartan was able to displace [ 125I]angiotensin II with a K i of 4.05 nM as compared to losartan (DuP 753) and tasosartan (WAY 126756), which had K i values of 25.2 nM and 46.6 nM, respectively. Similarly, in functional assays, irbesartan exhibited the highest functional potency to block angiotensin II-induced inositol trisphosphate (IP 3) turnover. The improved affinity of irbesartan for the angiotensin AT 1 receptor does not coincide with a concomitant increase in affinity for the angiotensin AT 2 receptor, as irbesartan and losartan exhibited the same low potency to displace [ 125I]angiotensin II in radioligand binding assays performed on membranes from PC-12w cells. In binding assays performed on peripheral tissues in rat, irbesartan bound to the angiotensin AT 1 receptor expressed in liver, adrenal, kidney and pituitary with an overall affinity closely approaching that of the high affinity peptidic antagonist [Sar 1, Ile 8]angiotensin II. Due to the higher affinity of irbesartan over other similar antagonists for the angiotensin AT 1 receptor in many tissues and its greater potency to block receptor activation, irbesartan may be quite useful in the study of the angiotensin AT 1 receptor and its role in controlling ingestive behaviours and, furthermore, shows great potential to improve the treatment of hypertension and other cardiovascular disease states.