Binding sites of valsartan, candesartan and losartan with angiotensin II receptor 1 subtype by molecular modeling

Bhuiyan, Mohiuddin Ahmed; Ishiguro, Masaji; Hossain, Murad; Nakamura, Takashi; Ozaki, Masanori; Miura, Shin-ichiro; Nagatomo, Takafumi

doi:10.1016/j.lfs.2009.05.001

Cited by 42 publications

(29 citation statements)

References 18 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Of interest, AZL has a unique moiety, a 5-oxo-1,2,4-oxadiazole, in place of a tetrazole ring (Kohara et al, 1996). Because the tetrazole ring of existing ARBs may interact with the Gln257, Lys199, or Asn295 residues in AT 1 receptors (Miura et al, 2006;Bhuiyan et al, 2009;Qin et al, 2009), the oxadiazolone in AZL may interact with these residues more strongly than with the tetrazole ring.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Ojima¹,

Igata²,

Tanaka³

et al. 2010

J Pharmacol Exp Ther

138

115

View full text Add to dashboard Cite

The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2Ј-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of 125 I-Sar 1 -Ile 8 -AII to human angiotensin type 1 receptors with an IC 50 of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC 50 value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC 50 values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC 50 values of 242.5, 191.6, Ͼ10,000, and Ͼ10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC 50 value of 9.2 nmol; this effect was resistant to washout (IC 50 value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC 50 values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC 50 value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pDЈ 2 value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings.

show abstract

Section: Discussionmentioning

confidence: 99%

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Ojima¹,

Igata²,

Tanaka³

et al. 2010

J Pharmacol Exp Ther

138

115

View full text Add to dashboard Cite

show abstract

“…Binding of ARBs to AT1R has been explored by structure activity relationships (Mire et al, 2005), modeling (Buhlmayer et al, 1991;Berellini et al, 2005;Miura et al, 2006;Bhuiyan et al, 2010aBhuiyan et al, , 2009b, conformational analysis (Masek et al, 1993;Polevaya et al, 2001;Zoumpoulakis et al, 2002), and receptor mutation studies (Ji et al, 1994;Schambye et al, 1995;Miura et al, 2008;Bhuiyan et al, 2010a). The latter approach was partly based on systematic screening efforts but more often hypothesis driven, i.e., exchanging specific amino acids known to be important in the binding properties of other receptors; of note, sitedirected mutagenesis studies have become an important way to experimentally test the predictions from the molecular modeling studies.…”

Section: F Modeling Of the At1r Binding Pocketmentioning

confidence: 99%

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

et al. 2013

View full text Add to dashboard Cite

“…So the present study was performed to determine if there is increased affinity of the non-peptide antagonists towards some specific mutants of the AT 1 receptor and to investigate the importance of the amino acid residues responsible for such observations. In saturation binding experiments, the data represent different levels of cell expression of the mutant receptors compared to the wild-type AT 1 -angiotensin II for the wild-type and N235R mutant of the AT 1 receptor, although F239R bound to the radioligand with significantly higher affinity whereas lower affinity with the ligand was found in the F239W mutant. It is evident from the competition binding study ( Table 2) that all the antagonists of this study showed higher binding affinity towards the mutants compared to the wild-type AT 1 receptor (candesartan, 3 -34-fold; valsartan, 3 -7-fold; losartan, 7 -19-fold; and telmisartan, 2 -5-fold).…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study we identified the binding sites of non-peptide angiotensin II (Ang II)-receptor antagonists with Ang II type 1 (AT 1 ) receptor by molecular modeling (1). We also showed the binding affinity and internalization behavior of the constitutively active mutant (CAM) N111G of AT 1 receptors in our earlier studies (2).…”

Section: Introductionmentioning

confidence: 97%

“…The AT 1 receptor is an important target for drug development because abnormalities in its function are linked to hypertension, water-electrolyte imbalance, hyperaldosteronism, cardiac hypertrophy, and heart failure (9). Ang II-receptor blockers (ARBs) are highly selective for AT 1 receptors. In addition to their blood pressure-lowering effects, ARBs have been shown to promote regression of left ventricular hypertrophy and decrease cardiovascular morbidity and mortality in patients with heart failure or hypertensive diabetic nephropathy with proteinuria (7).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Engineered Mutation of Some Important Amino Acids in Angiotensin II Type 1 (AT1) Receptor Increases the Binding Affinity of AT1-Receptor Antagonists

et al. 2010

Self Cite

View full text Add to dashboard Cite

Abstract. The present study was designed to examine the binding affinity and functional potency of selective angiotensin II type 1 (AT 1 )-receptor antagonists towards specific mutants of AT 1 receptor using site-directed mutagenesis. We also compared our results with the wild-type AT 1 receptor and investigated the possible reasons behind that. Both wild-type and mutant receptors were expressed in COS-7 cells and the binding affinities of the antagonists were determined by radioligand binding assay. Inhibition of agonist-stimulated inositol phosphate accumulation by the antagonists was also done. Substitution of asparagine 235 of intracellular loop 3 of the AT 1 receptor by arginine increased the binding affinity of the antagonists 5 -34-fold, whereas the increase in the binding affinity of the antagonists in the phenylalanine 239 mutant by arginine and tryptophan (F239R and F239W) were 3 -19-fold and 2 -15-fold higher, respectively, compared to the wildtype AT 1 receptor. The results suggested that substitution by a positively charged or sterically hindered amino acid in the AT 1 receptor allows it to interact with the acidic tetrazole moiety and carboxylate groups of the antagonists more strongly compared to the wild-type receptor. These findings may play an important role to change the binding affinity of the antagonists to an effective level for the pharmacological function of the drugs.

show abstract

Binding sites of valsartan, candesartan and losartan with angiotensin II receptor 1 subtype by molecular modeling

Cited by 42 publications

References 18 publications

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

Engineered Mutation of Some Important Amino Acids in Angiotensin II Type 1 (AT1) Receptor Increases the Binding Affinity of AT1-Receptor Antagonists

Contact Info

Product

Resources

About