First Reported Nonpeptide AT<sub>1</sub>Receptor Agonist (L-162,313) Acts as an AT<sub>2</sub>Receptor Agonist in Vivo

Wan, Yiqian; Wallinder, Charlotta; Johansson, Björn; Holm, Mathias; Arulprakasajothi, M.; Wu, Xiongyu; Botros, Milad; Karlén, Anders; Pettersson, Anders; Nyberg, Fred; Fändriks, Lars; Hallberg, A.; Alterman, Mathias

doi:10.1021/jm031031i

Cited by 46 publications

(39 citation statements)

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“…In this context, Wan et al (2004b) have recently described the first non-peptide, selective AT2 receptor agonist, Compound 21 (N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylph enyl)-5-isobutylthiophene-2-sulphonamide). Compound 21 was derived from a medicinal chemistry programme aimed at transforming the drug-like but non-selective AT1 and AT2 receptor agonist L-162313 (Wan et al, 2004a) into a selective AT2 receptor agonist. Compound 21 exhibits a Ki value of 0.4 nM for the AT2 receptor and a Ki > 10 mM for the AT1 receptor.…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of angiotensin AT₂ receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Bosnyak

Welungoda

Hallberg

et al. 2010

British J Pharmacology

134

103

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Background and purpose: Angiotensin type 2 receptor (AT2 receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT1 receptors). Recently, a novel non-peptide AT2 receptor agonist, Compound 21, was described, which exhibited high AT2 receptor selectivity. Experimental approach: Functional cardiovascular effects of the drug candidate Compound 21 were assessed, using mouse isolated aorta and rat mesenteric arteries in vitro and in conscious spontaneously hypertensive rats (SHR). Key results: Compound 21 evoked dose-dependent vasorelaxations in aortic and mesenteric vessels, abolished by the AT2 receptor antagonist, PD123319. In vivo, Compound 21 administered alone, at doses ranging from 50 to 1000 ng·kg Pharmacology (2010) 159, 709-716; doi:10.1111/j.1476-5381.2009.00575.x; published online 28 January 2010 British Journal ofKeywords: Compound 21; angiotensin; angiotensin AT2 receptor; spontaneously hypertensive rats; blood pressure; vascular function Abbreviations: Ang II, angiotensin II; AT1 receptor, angiotensin type 1 receptor; AT2 receptor, angiotensin type 2 receptor; MAP, mean arterial pressure; SHR, spontaneously hypertensive rat; WKY rat, Wistar-Kyoto rat IntroductionThe octapeptide angiotensin II (Ang II) is the main biologically active mediator of the renin-angiotensin system and plays an important role in cardiovascular function by influencing vascular tone, structure, fluid and electrolyte balance via direct effects on endothelial and smooth muscle cells (Widdop et al., 2003;Jones et al., 2008). Two main receptor subtypes have been identified as binding sites for Ang II: angiotensin type 1 receptor (AT1 recepter) and type 2 receptor (AT2 receptor) (de Gasparo et al., 2000); nomenclature follows Alexander et al., 2008). Ang II has similar affinity for both AT1 receptors and AT2 receptors, whereas CGP42112 and PD123319 are the prototypical examples of an agonist and antagonist, respectively, at the AT2 receptor subtype. On the other hand, compounds such as candesartan and losartan are selective AT1 receptor antagonists that are used clinically for the treatment of hypertension. It is well established that most of the cardiovascular effects induced by Ang II, such as vasoconstriction, water and salt retention, are mediated via AT1 receptor (de Gasparo et al., 2000;Carey, 2005). In contrast, it has been suggested that the function of the AT2 receptor is to counter-regulate AT1 receptor-mediated actions, mainly based on experiments in which AT2 receptor function was deduced from the effects of AT2 receptor blockade, or altered responses in genetically modified animal models of AT2 receptor overexpression or deletion. However, demonstration of AT2 receptor-mediated effects, particularly in an in vivo setting, has been hampered by a lack of non-peptide AT2 receptor selective agonists and antagonists that exhibit oral bioavailability. In this context, Wan et al. (2004b) have recently described the first non-peptide, selecti...

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Section: Introductionmentioning

confidence: 99%

“…Compound 21 was derived from a medicinal chemistry programme aimed at transforming the drug-like but non-selective AT1 and AT2 receptor agonist L-162313 (Wan et al, 2004a) into a selective AT2 receptor agonist. Compound 21 exhibits a Ki value of 0.4 nM for the AT2 receptor and a Ki > 10 mM for the AT1 receptor.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of angiotensin AT₂ receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Bosnyak

Welungoda

Hallberg

et al. 2010

British J Pharmacology

134

103

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“…This process gave the corresponding alcohols 14-18 in good yields. The alcohols (14)(15)(16)(17)(18) were then subsequently oxidized with pyridiniumchlorochromate in dichloromethane to give the (4-bromophenyl)-heterocyclic-methanones (19)(20)(21)(22)(23) in high yields.…”

Section: Chemistrymentioning

confidence: 99%

“…1). [17][18][19] The unsubstituted imidazole provided a good moiety to obtain high affinity, AT 1 /AT 2 selectivity as well as agonism. We have also shown that 0968 the unsubstituted imidazole could be combined with substituents other than iso-butyl in the 5-postion of the thiophene.…”

Section: Introductionmentioning

confidence: 99%

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Arulprakasajothi¹,

Wan²,

Murugaiah³

et al. 2010

Bioorganic & Medicinal Chemistry

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“…46 In addition, AT2R agonists that enhance the antiproliferative and apoptotic effect of AT2R expression are emerging. 47,48 These therapeutic options remain experimental or at the laboratory levels, yet these novel directions represent a new paradigm to intervene in the progression of renal failure in IgAN by reducing tubulointerstital injury.…”

Section: Future Therapeutic Targets For Iganmentioning

confidence: 99%

Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure

2004

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IgA nephropathy (IgAN) runs a highly variable clinical course with frequent involvement of tubulointerstitial damage. Notably, renal progression correlates more closely with the severity of tubulointerstitial lesions than with the degree of glomerular lesions In IgAN. Mesangial IgA deposition induces local release of cytokines, complement, and angiotensin II leading to glomerular inflammation. It remains unclear how mesangial IgA deposition leads to tubulointerstitial injury in IgAN. Moreover, IgA deposits are rarely detected in renal interstitium in IgAN. We hypothesize that mediators released from mesangial cells triggered by IgA deposition leads to activation of proximal tubular epithelial cells. Our preliminary findings implicate a glomerulotubular cross talk with mediators released from the mesangium contributing to the pathogenesis of tubulointerstitial damage in IgAN. We have also found the expression of angiotensin II subtype-1 receptor or angiotensin II subtype-2 receptor in proximal tubular epithelial cells differs from that of mesangial cells. One potential therapeutic approach is to counterbalance the growth-stimulatory effects of angiotensin II through subtype-1 receptor in tubular epithelial cells by subtype-2 receptor-mediated apoptosis and growth inhibition. These novel findings may provide clinicians new therapeutic approach for selective blockade of the RAS in IgAN.

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First Reported Nonpeptide AT₁Receptor Agonist (L-162,313) Acts as an AT₂Receptor Agonist in Vivo

Cited by 46 publications

References 24 publications

Stimulation of angiotensin AT₂ receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Stimulation of angiotensin AT₂ receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure

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First Reported Nonpeptide AT1Receptor Agonist (L-162,313) Acts as an AT2Receptor Agonist in Vivo

Cited by 46 publications

References 24 publications

Stimulation of angiotensin AT2 receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Stimulation of angiotensin AT2 receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure

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Product

Resources

About

First Reported Nonpeptide AT₁Receptor Agonist (L-162,313) Acts as an AT₂Receptor Agonist in Vivo

Stimulation of angiotensin AT₂ receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Stimulation of angiotensin AT₂ receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats