Distinctions between non-peptide angiotensin II AT1-receptor antagonists

Abstract

A far-reaching understanding of the molecular action mechanism of AT 1 -receptor antagonists (AIIAs) was obtained by using CHO cells expressing transfected human AT 1 -receptors. In this model, direct [ 3 H]-antagonist binding and inhibition of agonistinduced responses (inositol phosphate accumulation) can be measured under identical experimental conditions. Whereas preincubation with a surmountable AIIA (losartan) causes parallel shifts of the angiotensin II (Ang II) concentration-response curve, insurmountable antagonists also cause partial (i.e., 30% for irbesartan, 50% for valsartan, 70% for EXP3174,) to almost complete (95% for candesartan) reductions of the maximal response. The main conclusions are that all investigated antagonists are competitive with respect to Ang II. They bind to a common or overlapping site on the receptor in a mutually exclusive way. Insurmountable inhibition is related to the slow dissociation rate of the antagonist-receptor complex (t 1/2 of 7 minutes for irbesartan, 17 minutes for valsartan, 30 minutes for EXP3174 and 120 minutes for candesartan). Antagonistbound AT 1 -receptors can adopt a fast and a slow reversible state. This is responsible for the partial nature of the insurmountable inhibition. The long-lasting effect of candesartan, the active metabolite of candesartan cilexetil, in vascular smooth muscle contraction studies, as well as in in vivo experiments on rat and in clinical studies, is compatible with its slow dissociation from, and continuous recycling between AT 1 -receptors. This recycling, or 'rebinding' takes place because of the very high affinity of candesartan for the AT 1 -receptor. IntroductionAngiotensin II (Ang II), the major peptide hormone of the renin-angiotensin-aldosterone system (RAAS) exerts most of its biological actions by stimulating Ang II receptors of the AT 1 subtype. Among these actions, the increased growth and contractility of vascular smooth muscle cells and cardiac myocytes 1,2 and the secretion of aldosterone by adrenal glomerulosa cells play a central role in the hypertensive effect of Ang II. AT 2 -receptors constitute the other major Ang II receptor subtype.3-5 They are expressed in foetal tissues and, in adulthood, they may also participate in blood pressure (BP) regulation albeit to a lesser extent than the AT 1 -receptors.During the last decade, much effort has been spent in developing non-peptide antagonists for the AT 1 -receptor for the clinical treatment of hypertension and congestive heart failure.

Molecular characterisation of the interactions between olmesartan and telmisartan and the human angiotensin II AT1 receptor

“…A two‐step, two‐state model (Vauquelin et al ., 2001b, 2001c, 2001d), whereby the initial ARB (I) receptor (R) interaction yields a fast reversible/surmountable complex (IR) and where this complex may subsequently adopt a tight binding/insurmountable state (IR*), has already been proposed to explain the competitive and partially insurmountable properties of previously tested ARBs (that is irbesartan, valsartan, EXP3174 and candesartan), and readily explains the behaviour of olmesartan and telmisartan in functional experiments in this study.…”

“…From a structural point of view, olmesartan (Figure 8) and many of the previously tested ARBs (Berellini et al ., 2005) possess an acidic tetrazole group at the 2′‐position of their biphenylmethyl moiety (Mire et al ., 2005). Based on simulation studies, it was proposed that this moiety plays an essential role in the initial drug–receptor binding process (Vauquelin et al ., 2001c). Because the initial I+R↔IR interaction is similar for these ARBs, differences in kinetic binding properties likely result from the ability of the ARB to stabilize the IR* complex.…”

“…To explain the changes observed in dose–response curves for surmountable and insurmountable ARBs, a two‐state, two‐step antagonist AT 1 receptor kinetic model that relates to slow dissociation of the ARB from the AT 1 receptor has been proposed (Fierens et al ., 1999b; Vanderheyden et al ., 2000a; Vauquelin et al ., 2001c, 2001d). So, although all ARBs share a common mechanism of action, differences in molecular structure may contribute to differences in binding kinetics and pharmacological activity.…”

“…Telmisartan (BIBR 277) distinguishes itself among the other ARBs by its long plasma half‐life (∼24 h) (White et al ., 2004) and has been reported to dissociate slowly from the AT 1 receptor (Maillard et al ., 2002; Kakuta et al ., 2005). Application of the two‐state, two‐step kinetic model for ARBs suggests that slow receptor dissociation should result in a high degree of insurmountability; (Vauquelin et al ., 2001c) however, in vitro studies have shown that telmisartan produces only a ∼50% reduction in the maximal Ang II‐mediated response (Wienen et al ., 1993; Schambye et al ., 1994). Among the potential explanations for this discrepancy are structural differences compared with related ARBs.…”

Long-lasting angiotensin type 1 receptor binding and protection by candesartan: comparison with other biphenyl-tetrazole sartans

“…When the concentration is further increased, these antagonists still produce rightward shifts of the dose-response curve, but the maximal stimulation will not decline any further. Several theories were proposed to explain insurmountable Ang II receptor blocker behaviour in molecular terms [14], but whether or not this involved non-competitive antagonism (i.e. antagonists that do not bind to the same site at the receptor as Ang II [15]) remained a matter of controversy.…”