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G J Moore

Publications and source records attributed to G J Moore.

At least 109 records · Page 6Linked to original sources
PubMed1986

Proton magnetic resonance studies of angiotensin II conformation: cis-trans isomerism in sarcosine7-containing analogs.

1H-NMR spectra for the angiotensin agonist sarcosine-(Sar)Arg-Val-Tyr-Ile-His-Sar-Phe [( Sar1,Sar7]Ang II) and the antagonist Sar-Arg-Val-Tyr-Ile-His-Sar-Ile in dimethylsulfoxide-d6 were examined at 400 MHz. Splitting of the resonances for Tyr, His, and Sar protons revealed that the His6-Sar7 peptide bond existed in both cis and trans forms, with one isomer predominating in the ratio 5:1 in both peptides. Comparison of the chemical shifts for the His6 and Phe8 ring protons in these peptides suggested a His/Phe stacking interaction in [Sar1,Sar7]Ang II which is important for agonist activity.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1986

Structure-activity relationships for the competitive angiotensin antagonist [sarcosine,O-methyltyrosine4]angiotensin II (sarmesin).

Analogues of the competitive angiotensin antagonist [Sar1,Tyr(Me)4]ANG II (sarmesin) in which the sarcosine-1, O-methyltyrosine-4, and phenylalanine-8 residues were modified have been synthesized by the solid-phase method. The agonist and antagonist potencies of the 23 peptides synthesized were determined in the rat isolated uterus assay. At position 1, replacement of Sar with Asp, Ala, or Pro gave inactive analogues, and deletion of the N-terminal amino acid produced inactive heptapeptides for all analogues investigated. At position 4, substitution of Tyr with Tyr(Et), D-Tyr, D-Phe, Ile, Thr, or Hyp resulted in inactive analogues, whereas substitution of Phe gave a potent competitive antagonist (pA2 = 7.9), which retained significant agonist activity (22%). For position 8, [Sar1,Tyr(Me)4,Ile8]ANG II and [Sar1,Phe4,Ile8]ANG II were weaker antagonists (pA2 = 6.6 and 6.7, respectively) than [Sar1,Ile8]ANG II (pA2 apparent = 8.1) and, moreover, were reversible competitive antagonists. These findings demonstrate that the structural requirements for receptor blockade by sarmesin are remarkably stringent--modifications at positions 1, 4, and 8 markedly reduce the antagonist activity of this peptide.

Angiotensin II↗
PubMed1985

Comparison of angiotensin receptors in isolated smooth muscle tissues by photoaffinity labelling.

The isolated rat uterus and rabbit aorta were photolabelled with [Azidobenzoic acid 1, isoleucine8]angiotensin II ([AB', Ile8]ANG II) and dose-response curves to angiotensins II and III were determined before and after the irreversible labelling procedure. The data obtained were used to calculate affinities, efficacies and 'spare' receptors for angiotensins II and III. In the rat uterus angiotension II was the higher affinity ligand, whereas in the rabbit aorta angiotensins II and III had similar affinities. 'Spare' receptors were present for both ligands in both tissues. In the rat uterus ANG II and ANG III had similar efficacies, whereas in the rabbit aorta ANG II was the more efficacious ligand. Angiotensin receptors in the rabbit aorta, rat uterus, and rat portal vein appear to be substantially different from one another, and point to the possibility of different functional roles for angiotensins II and III in different smooth muscle tissues. For the vascular tissues, tachyphylaxis to angiotensin was more marked after irreversible labelling than before, suggesting that the mechanism of angiotensin tachyphylaxis is receptor deactivation.

Affinity Labels↗
PubMed1985

Angiotensin as a model for hormone--receptor interactions.

Proton magnetic resonance and chemical reactivity studies have demonstrated the presence of a tyrosine charge relay system in angiotensin which is analogous to the serine charge relay system present at the active site of serine proteases. Receptor activation by angiotensin can be explained by electronic effects deriving from an interaction of the charge relay system with stacking of the histidine and phenylalanine rings. Experiments with serine protease inhibitors suggest the possibility that mechanistic features of the interaction of angiotensin with its receptors may apply to other 'phenoxyl' hormones including certain peptides, steroids and catecholamines.

Angiotensin II↗
PubMed1985

Synthesis and biological activities of analogues of angiotensins II and III containing O-methyltyrosine and D-tryptophan.

Analogues of angiotensin II and III (ANG II and ANG III) in which the tyrosine and/or phenylalanine residues were substituted have been synthesized by the solid-phase method and purified by (carboxymethyl)cellulose chromatography and reversed-phase HPLC. The antagonist and agonist potencies of these peptides were determined in the rat isolated uterus assay. [Sar1,Tyr(Me)4]ANG II, [Tyr(Me)3]ANG III, [Sar1,D-Trp4]ANG II, [D-Trp3]ANG III, [Sar1,D-Trp8]ANG II, [D-Trp7]ANG III, [Sar1,Tyr(Me)4,Ile8]ANG II, [Tyr(Me)3,Ile7]ANG III, [Sar1,D-Trp4,Ile8]ANG II, [D-Trp3,Ile7]ANG III, [Sar1,Tyr(Me)4,D-Trp8]ANG II, and [Tyr(Me)3,D-Trp7]ANG III had antagonist activities (pA2) respectively of 8.1, less than 6, less than 6, less than 6, (7.7), (6.7), 7.2, less than 6, less than 6, less than 6, 7.1, and less than 6. The agonist activity of each peptide was less than 0.1% of that of ANG II. Analogues in which only the Phe residue was substituted were not readily reversible in the bioassay, whereas analogues in which only the Tyr residue or both the Tyr and Phe residues were substituted were reversible antagonists. Peptides that were twice substituted had lower antagonist activities than peptides having a single aromatic residue substitution. Substitution of the Tyr residue in ANG II, but not ANG III, provides a new route for the synthesis of potent and competitive angiotensin antagonists. Differences in the biological properties of ANG II and ANG III analogues substituted at the Tyr residue suggest different binding/conformation requirements for the two endogenous ligands at angiotensin receptors in smooth muscle.

Angiotensin II↗
PubMed1985

Structure-desensitization relationships of angiotensin analogues in the rat isolated uterus.

The desensitizing potencies of angiotensin II (ANG II) analogues modified at positions 1, 2, 4, 7, and 8 have been examined in the rat isolated uterus assay by determining the time of recovery of the half-maximal concentration (EC50) response to angiotensin II after treatment of the tissues with a high dose (10(-5) M) of each analogue for 2 min. The magnitude of the desensitization effect was substituent dependent in the following manner: position 1, sarcosine (Sar) greater than Asp greater than des-Asp; position 2, Arg greater than Sar; position 4, Tyr greater than Tyr(Me) approximately Phe; position 7, 3,4-dehydroproline (Dpr) greater than Pro greater than thioproline (Tpr) greater than Sar; position 8, Ile greater than D-Trp greater than Ala greater than Phe. The "additivity" rule applied to these structure-desensitization relationships and the most potent desensitizer, requiring 3 h for reestablishment of the EC50 response, was [Sar1, Dpr7, Ile8]-ANG II. The desensitizing potencies of these analogues did not correlate with agonist or antagonist activities and demonstrated that the angiotensin-mediated tissue desensitization process has unique structural determinants. Methylation or elimination of the tyrosine hydroxyl group of strong desensitizers virtually eliminated the desensitization effect, implicating the phenoxyl moiety in the mechanism of desensitization. The initial phase of recovery of angiotensin responsiveness after desensitization by several analogues appeared to obey first-order kinetics. The results are discussed in the contexts of both one- and two-site receptor models.

Angiotensin II↗
PubMed1985

Kinetics of acetylation-deacetylation of angiotensin II. Intramolecular interactions of the tyrosine and histidine side-chains.

The possible existence of intramolecular interactions involving the tyrosine and histidine residues in angiotensin II has been investigated by measuring the reactivities of the functional groups in the molecule. Angiotensin II catalyzed the hydrolysis of p-nitrophenylacetate in the pH range 6.6-8.2 at higher rates than were consistent with the reactivities of the free constituent functional groups, and had 2-4% of the activity of chymotrypsin between pH 6.6 and 7.5. Treatment of angiotensin II with acetic anhydride demonstrated that the tyrosine hydroxyl and the imidazole side-chain in angiotensin II acetylated and deacetylated at markedly higher rates than for the free amino acids, indicating increased nucleophilicities and the presence of intrinsic deacetylation mechanisms for these residues in angiotensin II. These findings are consistent with the presence of tyrosine hydroxyl-histidine-carboxylate charge relay system in ANG II in aqueous environments, and suggest that ANG II may act at membrane receptors by a mechanism which is analogous to that operating in serine proteases.

Acetic Anhydrides↗
PubMed1984

NMR studies on angiotensin II: histidine and phenylalanine ring stacking and biological activity.

The conformations of angiotensin II and the antagonist [Sar1, Ile8]angiotensin II in dimethylsulfoxide have been examined by high resolution proton magnetic resonance spectroscopy at 400 MHz. The chemical shifts for the aromatic protons of the phenylalanine residue in angiotensin II are consistent with shielding and restricted rotation for this side-chain. The chemical shifts for the histidine C2 and C4 protons in angiotensin II also indicate shielding, whereas these same protons in the antagonist [Sar1, Ile8]angiotensin II do not demonstrate this shielding influence. These findings suggest a stacking interaction for the histidine and phenylalanine side-chains in angiotensin II which is important for activating angiotensin receptors.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1984

A new approach to angiotensin antagonists: methylation of the tyrosine hydroxyl in angiotensin II.

[Sar1, Tyr(Me)4]angiotensin II, synthesized by the solid phase method and purified by ion-exchange chromatography and reversed-phase HPLC, was found to inhibit the contractile response to angiotensin II in the rat isolated uterus and inhibit the pressor response to angiotensin II in the vagotomized ganglion-blocked rat. In the rat isolated uterus Schild plots gave a pA2 of 8.1, and a slope of 0.9 indicative of competitive inhibition. In the rat pressor assay, infusion of the analogue at a rate of 500ng/kg/min caused a parallel displacement of the dose-response curve to ANG II to the right. In contrast, the classical angiotensin inhibitor [Sar1, Ile8] ANG II appeared to demonstrate non-competitive inhibition in both the rat isolated uterus and the pressor assays. The phenolic hydroxyl of phenoxide anion of Tyr4 in angiotensin II appears to be critical for the activation of angiotensin receptors in smooth muscle. Alkylation of the tyrosine residue in angiotensin analogues provides a new route for the synthesis of potent competitive antagonists of angiotensin.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1984

A cyclic angiotensin antagonist: [1,8-cysteine]angiotensin II.

[Cys(S-acetamidomethyl)1,8]angiotensin II has been synthesized by the solid-phase method and purified by carboxymethylcellulose chromatography and reversed-phase HPLC. Treatment of this peptide with iodine gave the cyclic octapeptide [Cys1,8]angiotensin II, which was isolated by Sephadex G-25 chromatography and reversed-phase HPLC. Comparison of the circular dichroism spectra of the open-chain and cyclic peptides, respectively, demonstrated the existence of a disulfide bond with right-handed chirality in the cyclic peptide. In the isolated rat uterus assay, the open-chain peptide was found to be a potent antagonist of angiotensin II, having approximately 10% of the activity of [Sar1, Ile8]angiotensin II, and the cyclic peptide had about 10% of the antagonist potency of its open-chain synthetic precursor.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1984

Photoaffinity labeling of the rat isolated portal vein: determination of affinity constants and "spare" receptors for angiotensins II and III.

Photoaffinity labeling of the isolated rat portal vein with [azidobenzoic acid, isoleucine]angiotensin II resulted in selective partial inactivation of angiotensin receptors without affecting norepinephrine receptors. Establishment of dose-response curves to angiotensin II and III before and after photoaffinity labeling has permitted the calculation of "spare" receptors and affinity constants for angiotensins II and III. Spare receptors appear to exist for angiotensin II (greater than 60%) but not for angiotensin III. Furthermore, the data indicate that angiotensin III has a higher binding affinity (K = 6 X 10(-8) M) than angiotensin II (K = 3 X 10(-7) M), but is considerably less potent than angiotensin II in eliciting the contractile response. If angiotensins II and III act at the same receptors in the portal vein, angiotensin III could inhibit the constricting action of angiotensin II and thereby play a role in the angiotensin-mediated control of portal venous capacity.

Affinity Labels↗