ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT<sub>2</sub> AND ENDOMETRIAL AT<sub>1</sub> RECEPTORS ARE DOWN‐REGULATED DURING GESTATION

Nielsen, A. H.; Schauser, Kirsten; Winther, Henrik; Dantzer, V.; Poulsen, Knud

doi:10.1111/j.1440-1681.1997.tb01193.x

Cited by 38 publications

(28 citation statements)

References 25 publications

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“…Myometrial membranes were prepared from porcine uteri according to the method of Nielsen et al . (18). Potential interference by binding to AT 1 receptors was blocked by the addition of 1 μ m losartan.…”

Section: Porcine (Pig) Myometrial Membrane At2 Receptor Binding Assaymentioning

confidence: 99%

Synthesis and AT₂ receptor‐binding properties of angiotensin II analogues

Rosenström

Sköld

Lindeberg

et al. 2004

The Journal of Peptide Research

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The present study investigates the importance of the amino acid side chains in the octapeptide angiotensin II (Ang II) for binding to the AT2 receptor. A Gly scan was performed where each amino acid in Ang II was substituted one-by-one with glycine. The resulting set of peptides was tested for affinity to the AT2 receptor (porcine myometrial membranes). For a comparison, the peptides were also tested for affinity to the AT1 receptor (rat liver membranes). Only the substitution of Arg2 reduced affinity to the AT2 receptor considerably (92-fold when compared with Ang II). For the other Gly-substituted analogues the affinity to the AT2 receptor was only moderately affected. To further investigate the role of the Arg2 side chain for receptor binding, we synthesized some N-terminally modified Ang II analogues. According to these studies a positive charge in the N-terminal end of angiotensin III [Ang II (2-8)] is not required for high AT2 receptor affinity but seems to be more important in Ang II. With respect to the AT1 receptor, [Gly2]Ang II and [Gly8]Ang II lacked binding affinity (Ki > 10 microM). Replacement of the Val3 or Ile5 residues with Gly produced only a slight decrease in affinity. Interestingly, substitution of Tyr4 or His6, which are known to be very important for AT1 receptor binding, resulted in only 48 and 14 times reduction in affinity, respectively.

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Section: Porcine (Pig) Myometrial Membrane At2 Receptor Binding Assaymentioning

confidence: 99%

Synthesis and AT₂ receptor‐binding properties of angiotensin II analogues

Rosenström

Sköld

Lindeberg

et al. 2004

The Journal of Peptide Research

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“…Compounds 3−6 were evaluated for affinity in a radioligandbinding assay by displacement of [ 125 I]Ang II from AT 2 receptors in pig uterus membranes as described previously by Nielsen et al 21 The natural substrate Ang II and the selective AT 1 receptor antagonist losartan were used as reference substances. 22 The results of the binding study are presented in Table 1.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Wallinder

Sköld

Botros

et al. 2014

ACS Med. Chem. Lett.

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Migration of the methylene imidazole side chain in the first reported selective drug-like AT 2 receptor agonist C21/M024 (1) delivered the AT 2 receptor antagonist C38/M132 (2). We now report that the AT 2 receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein. KEYWORDS:AT 2 receptor, nonpeptide ligands, agonist, antagonist, C21/M024, C38/M132 T he sartans (angiotensin II receptor blockers, ABRs) have been on the market as antihypertensives for more than two decades and act as selective antagonists at the angiotensin II AT 1 receptor. More recently, the angiotensin AT 2 receptor has emerged as a new target for drug intervention.1−3 In 2004, the first selective and drug-like AT 2 receptor agonist C21/ M024 (1) was disclosed, 4 and thereafter, a series of structural analogues with agonistic properties have been reported. 5,6 The activation of the AT 2 receptor is known to render a large number of diverse biological responses. 7,8 For example, receptor activation stimulates neurite outgrowth in neuronal cells, which is one of the first steps in neuronal differentiation. 9In healthy adults the AT 2 receptor expression is low and mainly found in renal, cardiovascular, and brain tissues. 7,8 Notably, during certain pathological conditions, such as myocardial infarction, vascular injury, brain ischemia, renal failure, and cutaneous wounds, the AT 2 receptor expression is significantly up-regulated. 7,8 Recently, several studies conducted in experimental disease models have revealed that the selective potent AT 2 receptor agonist 1 acts as an anti-inflammatory agent and exerts pronounced tissue protective effects in particular in cardiovascular and renal disease. Hence, the compound has had a large impact on the view of the AT 2 receptor as a drug target.1,9−14 In addition, the AT 2 receptor is a promising drug target for antagonists. Thus, the AT 2 receptor antagonist EMA401 has demonstrated convincing efficacy data in patients suffering from neuropathic pain (postherpetic neuralgia) in a phase II study. 3 We discovered that migration of the methylene imidazole substituent of 1 from the para to the meta substitution pattern delivered a selective AT 2 receptor antagonist, compound C38/M132 (2) (Figure 1). 15,16 Thus, a minor structural alteration resulted in the interconversion of a selective AT 2 receptor agonist to a selective AT 2 receptor antagonist.Herein, we report the synthesis and biological evaluation of four AT 2 receptor ligands, the biphenyl derivatives, and regioisomers, 3, 4, 5, and 6 (Figure 2), and that the relative position of the imidazole and isobutyl substituent determines the functional outcome.The

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“…26,27 The natural substrate Ang II, the selective AT 1 receptor antagonist losartan, 28 and the selective AT 2 receptor antagonist PD 123,319 29 were used as reference substances (Fig. 2).…”

Section: Binding Assaysmentioning

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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ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT₂ AND ENDOMETRIAL AT₁ RECEPTORS ARE DOWN‐REGULATED DURING GESTATION

Cited by 38 publications

References 25 publications

Synthesis and AT₂ receptor‐binding properties of angiotensin II analogues

Synthesis and AT₂ receptor‐binding properties of angiotensin II analogues

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

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ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT2 AND ENDOMETRIAL AT1 RECEPTORS ARE DOWN‐REGULATED DURING GESTATION

Cited by 38 publications

References 25 publications

Synthesis and AT2 receptor‐binding properties of angiotensin II analogues

Synthesis and AT2 receptor‐binding properties of angiotensin II analogues

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands

Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Contact Info

Product

Resources

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ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT₂ AND ENDOMETRIAL AT₁ RECEPTORS ARE DOWN‐REGULATED DURING GESTATION

Synthesis and AT₂ receptor‐binding properties of angiotensin II analogues

Synthesis and AT₂ receptor‐binding properties of angiotensin II analogues

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands