title: 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'-¿1H-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.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104-6046, USA. hines@pharm.med.upenn.edu
authors.forename: J
authors.initials: J
authors.lastname: Hines
authors.forename: S J
authors.initials: SJ
authors.lastname: Fluharty
authors.forename: R R
authors.initials: RR
authors.lastname: Sakai
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007457:Iodine Radioisotopes; D000077405:Irbesartan; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D016716:PC12 Cells; D010902:Pituitary Gland / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007457:Iodine Radioisotopes; D011743:Pyrimidines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C086167:tasosartan; D000077405:Irbesartan; D019808:Losartan