title: Molecular characterisation of the interactions between olmesartan and telmisartan and the human angiotensin II AT1 receptor.
abstract: OBJECTIVE
  Whereas some angiotensin II (Ang II) type 1 receptor blockers (ARBs) produce surmountable antagonism of AT(1) receptors, others such as olmesartan and telmisartan display varying degrees of insurmountability. This study compared the molecular interactions of olmesartan and telmisartan with the human AT(1) receptor, using well characterised in vitro methods and model systems.
  
  
  METHODS
  CHO-K1 cells that stably express human AT(1) receptors (CHO-hAT(1) cells) were used in several pharmacological studies of olmesartan and telmisartan, including direct radioligand binding and inhibition of Ang II-induced inositol phosphate (IP) accumulation.
  
  
  RESULTS
  Both ARBs were found to be competitive antagonists that displayed high affinity, slow dissociation, and a high degree of insurmountability for the AT(1) receptor (the latter greater with olmesartan). Their receptor interactions could be described by a two-step process with the initial formation of a loose complex (IR) and subsequent transformation into a tight binding complex (IR*). In washout experiments, [(3)H] telmisartan dissociated from the receptor with a half-life of 29 min and the Ang II-mediated IP accumulation response was 50% maximally restored within 24 min, whereas values for [(3)H] olmesartan were 72 min and 76 min, respectively.
  
  
  CONCLUSIONS
  The high degree of insurmountability, slow dissociation, and high affinity of olmesartan for its receptor may relate to its ability to stabilise IR* via the carboxyl group of its imidazole core. In comparison, telmisartan displays a less potent interaction with the receptor.
authors.affiliation: Departments of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: M T
authors.initials: MT
authors.lastname: Le
authors.forename: M K
authors.initials: MK
authors.lastname: Pugsley
authors.forename: G
authors.initials: G
authors.lastname: Vauquelin
authors.forename: I
authors.initials: I
authors.lastname: Van Liefde
mesh_terms: D000804:Angiotensin II / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D000077333:Telmisartan; D013777:Tetrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D007093:Imidazoles; D007295:Inositol Phosphates; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014316:Tritium; D000804:Angiotensin II; C437965:olmesartan; D000077333:Telmisartan