In vitro pharmacological characterization of a new selective angiotensin AT1 receptor antagonist, UR-7280

Arriba, Alberto Fernández de; Gómez-Casajús, Luis A.; Cavalcanti, F. L.; Almansa, Carmen; García-Rafanell, Julián; Forn, J.

doi:10.1016/s0014-2999(96)00794-7

Cited by 36 publications

(20 citation statements)

References 16 publications

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“…In this respect, slow receptor dissociation has been proposed to contribute to the long-lasting clinical action of antagonists for angiotensin AT 1 (Wienen et al, 1993;Aiyar et al, 1995;De Arriba et al, 1996;Unger, 1999), histamine H 1 (Anthes et al, 2002), nicotinic (el-Bizri andClarke, 1994), adrenergic ␣ 2A (Kukkonen et al, 1997), serotonergic 5-HT 3 (Blower, 2003), and muscarinic M 3 (Swinney, 2004) receptors. In this respect, recent simulation studies (Vauquelin and Van Liefde, 2006) reveal that, compared with a fast dissociating antagonist, prolonged in vivo receptor occupancy should take place when the antagonistreceptor complexes dissociate much slower than the antagonist gets eliminated.…”

Section: Discussionmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Lindström¹,

Mentzer²,

Påhlman³

et al. 2007

J Pharmacol Exp Ther

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We compared the neurokinin 1 receptor (NK 1 R) antagonists aprepitant, CP-99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-methyl]napthamide]] with respect to receptor interactions and duration of efficacy in vivo. In Ca 2ϩ mobilization assays (fluorometric imaging plate reader), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP). In reversibility studies, antagonists were present for 30 min before washing, and responses to SP were repeatedly measured afterward. The compounds were administered i.p. to gerbils, and the gerbil foot tap (GFT) response was monitored at various time points. The NK 1 R receptor occupancy for aprepitant was determined in striatal regions. Levels of compound in brain and plasma were measured. Antagonists were equipotent at human NK 1 R and acted competitively with SP. After preincubation, aprepitant and ZD6021 attenuated the maximal responses, whereas CP-99994 only shifted the SP concentration-response curve to the right. The inhibitory effect of CP-99994 was over within 30 min, whereas for ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced maximal inhibition lasting at least 60 min. CP-99994 (3 mol/kg) inhibited GFT by 100% 15 min after administration, but the effect declined rapidly together with brain levels thereafter. The efficacy of ZD6021 (10 mol/kg) lasted 4 h and correlated well with brain levels. Aprepitant (3 mol/kg) inhibited GFT and occupied striatal NK 1 R by 100% for Ͼ48 h despite that brain levels of compound were below the limit of detection after 24 h. Slow functional reversibility is associated with long-lasting in vivo efficacy of NK 1 R antagonists, whereas the efficacy of compounds with rapid reversibility is reflected by their pharmacokinetics.The neurokinins substance P (SP), neurokinin (NK) A (NKA), and NKB belong to the tachykinin peptide family (Severini et al., 2002). The tachykinin receptors are divided into three subtypes: NK 1 R, NK 2 R, and NK 3 R. The rank order of potency of the endogenous tachykinins are: for NK 1 R, SP Ն NKA Ͼ NKB; for NK 2 R, NKA Ͼ NKB Ͼ SP; and for NK 3 R, NKB Ͼ NKA Ͼ SP (for review, see Pennefather et al., 2004). Hemokinin-1 and endokinins A and B are relatively new mammalian members of the tachykinin family but appear to have similar receptor pharmacology as SP (Page, 2006). On the other hand, endokinins C and D have negligible affinity for known NK receptors (Page, 2006).Preclinical research has implicated especially the NK 1 R as being involved in several pathological disorders, including emesis, asthma, psychiatric disorders, gastrointestinal disorders, pain, migraine, inflammation, and urinary bladder disorders. This has led to the subsequent development of selective and potent NK 1 R antagonists (for recent review, see Quartara and Altamura, 2006). However, so far, only aprepitant has reached the market for treatment of chemothe...

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Section: Discussionmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Lindström¹,

Mentzer²,

Påhlman³

et al. 2007

J Pharmacol Exp Ther

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“…[29][30][31][32] The same profile also emerges when comparing radioligand binding studies on cell membranes involving pre and coincubation experiments. 22,[33][34] The ability of certain antagonists to decrease the maximal effect of Ang II is therefore the result of the experimental set-up (i.e., antagonist preincubation) and should not be ascribed to non-competitive behaviour (Figure 1). In fact, competitive antagonists are perfectly able to decrease the maximal response to Ang II under these conditions, provided that their blockade is so longlasting that it cannot be 'surmounted' during the subsequent brief challenge with Ang II.…”

Section: At 1 -Receptor Antagonists (Aiias) Are Competitivementioning

confidence: 99%

“…17,22,24,25,38,45,52 In contrast, the precursor molecules for candesartan (candesartan cilexetil) and EXP3174 (losartan) are totally surmountable and devoid of the carboxyl group. 12,13 However, the mere presence of two acidic groups is not suf- …”

Section: Link Between Insurmountable Antagonism and Chemical Structurementioning

confidence: 99%

“…[9][10][11][12][13] Several theories have been proposed to explain the differences in behaviour of the AIIAs at the molecular level. These include noncompetitive antagonist action owing to the presence of allosteric antagonist binding sites on the receptor, 14 antagonist-mediated conformational changes of the receptor that render them refractory to stimulation, 15,16 slow dissociation of the antagonist-receptor complex or even irreversible antagonist binding, [17][18][19][20][21][22][23] slow removal of the antagonist from tissue compartments, cells or matrix surrounding the receptor, 24,25 co-existence of different receptor subpopulations, 7 and the ability of the antagonist to affect the internalisation of AT 1 -receptors within the cell. 9 Discrimination between surmountable and insurmountable AIIAs can also be made by investigating their effect on Ang II-mediated responses in isolated cell lines.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

Vauquelin¹,

Fierens²,

Verheijen³

et al. 2001

J Renin Angiotensin Aldosterone Syst

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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.

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“…Whereas all antagonists possess a negatively charged tetrazole ring, it is noteworthy that candesartan, EXP3174 and many other insurmountable antagonists also possess a second acidic, carboxyl group. [12][13][14][15][16][17][18] Interestingly, candesartan cilexetil and losartan, the precursor molecules for candesartan and EXP3174, are totally surmountable and devoid of this carboxyl group. 7,10 The carboxyl group of candesartan and EXP3174 is therefore likely to play a pivotal role in the formation of the tight antagonist-receptor complexes.To verify this hypothesis, site-directed mutagenesis studies, involving the substitution of certain basic amino acids of the AT 1 -receptor into neutral ones, have been initiated.…”

Section: Introductionmentioning

confidence: 99%

Role of basic amino acids of the human angiotensin type 1 receptor in the binding of the non-peptide antagonist candesartan

Vauquelin¹,

Fierens²,

Gáborik

et al. 2001

J Renin Angiotensin Aldosterone Syst

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To explain the insurmountable/long-lasting binding of biphenyltetrazole-containing AT 1 with the proposed model, it cannot be excluded that both amino acid residues are important for the structural integrity of the AT 1 -receptor with respect to its ligand binding properties. IntroductionThe therapeutic use of selective, non-peptide antagonists for the angiotensin II type 1 (AT 1 )-receptor in the treatment of hypertension is well established.1 Experiments with Chinese Hamster Ovary cells, which have been permanently transfected with the gene coding for the human AT 1 -receptor (CHO-hAT 1 cells) have shed new light on the molecular mechanism of action of these AT 1 -receptor antagonists. One of the major findings is that these antagonists exhibit a competitive type of interaction with angiotensin II (Ang II) on the receptor: they bind to a common or overlapping site on the receptor in a mutually exclusive way.

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In vitro pharmacological characterization of a new selective angiotensin AT1 receptor antagonist, UR-7280

Cited by 36 publications

References 16 publications

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Distinctions between non-peptide angiotensin II AT1-receptor antagonists

Role of basic amino acids of the human angiotensin type 1 receptor in the binding of the non-peptide antagonist candesartan

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