Synthesis of [3,5-3H2-Tyr23]-β-corticotrophin-(1–24)-tetracosapeptide

Brundish, Derek E.; Wade, Roy

doi:10.1039/p19730002875

Cited by 29 publications

(21 citation statements)

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“…In order to minimize the loss of peptides through adsorption to surfaces, plastic apparatus was used whenever possible, instead of glassware. This (Brundish & Wade, 1973). All these analogues were found to have full biological activity.…”

Section: Methodsmentioning

confidence: 69%

On the Metabolism of Two Adrenocorticotrophin Analogues

Baker¹,

Bennett²,

Hudson³

et al. 1976

Clinical Endocrinology

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The metabolism of Synacthen (corticotrophin-(1--24)-tetracosapeptide) and C-41795-Ba ([D-Ser1,Lys17,Lys18]-corticotrophin-(1--18)-octadecapeptide amide) have been compared in the rat following intravenous injection. Using Synacthen and C-41795-Ba labelled with tritium it was possible to follow the tissue distribution of the two peptides. The kidney was shown to concentrate intact peptide and fragments of both peptides. Autoradiography of perfused kidney sections demonstrated the uptake of radioactivity into the lysosomes of the kidney proximal tubule cells. Comparison of the distribution of radioactive products formed from the tetracosapeptide labelled in different positions indicates that, prior to renal uptake, metabolism is taking place at other sites in the body. It is suggested that rapid cleavage occurs extracellularly at or near the N- and C-termini. Then large fragments remaining in the circulation, together with any intact material, are filtered through the glomerulus and are taken up by endocytosis into the proximal tubule cells of the kidney. The synthetic N- and C-terminal protection of the octadecapeptide appears to inhibit the extracellular attack and so the concentration of intact peptide in the kidneys is initially higher than the tetracosapeptide. Although concentrations of radioactivity in other tissues are low in comparison with the kidneys, the quantities are quite high when the weight of the tissues are considered. Chromatographic analysis of this radioactivity reveals that the octadecapeptide gives rise to much higher tissue levels of intact peptide and we believe that this acts as a depot and gives rise to the sustained blood concentrations and prolonged biological effects observed with this peptide.

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Section: Methodsmentioning

confidence: 69%

On the Metabolism of Two Adrenocorticotrophin Analogues

Baker¹,

Bennett²,

Hudson³

et al. 1976

Clinical Endocrinology

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“…Chemicals were of AR grade whenever possible. [(3,5-3H)Tyr2]-Corticotrophin-(l-24)-tetracosapeptide (29 Ci/mmol), [(3,5-3H)Tyr23]-corticotrophin-(l-24)-tetracosapeptide (34-5 Ci/mmol), [(4-3H)Phe7]-corticotrophin-(l-24)-tetracosapeptide (24-7 Ci/mmol), Lys17, Lys18]-corticotrophin-(l-18)-octadecapeptide amide (17-05 Ci/ mmol) (Brundish «fe Wade, 1973Brundish, Martin «fe ) and D-Ser-[3,5-3H]-Tyr were synthesized at CIBA-GEIGY Laboratories by Dr D. E. Brundish, Mr J. R. Martin and Dr R. Wade. Unlabelled corticotrophin-(l-24)-tetracosapeptide and [D-Ser1,Lys17,-Lys18]-corticotrophin-(l-18)-octadecapeptide amide were kindly supplied by Dr W. Rittel, CIBA-GEIGY Ltd, Basle, Switzerland.…”

Section: Methodsmentioning

confidence: 99%

Distribution and Degradation of Two Tritium-Labelled Corticotrophin Analogues in the Rat

Bennett¹,

McMartin²

1979

Journal of Endocrinology

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The distribution and degradation of corticotrophin-(1--24)-tetracosapeptide specifically labelled with tritium at Tyr2, Phe7 or Tyr23 and [D-Ser1, Lys17, Lys18]-corticotrophin-(1--18)-octadecapeptide amide labelled at Tyr2 were studied at various times after intravenous injection into rats. By characterizing the radioactivity in plasma and various tissues, an overall picture of the metabolic handling of the two peptides emerged. The peptides left the circulation rapidly, entering mainly muscle and skin where they were extensively degraded. The D-Ser1-containing analogue was less rapidly degraded and intact peptide persisted in muscle and skin for up to 1 h. This peptide probably returned to the circulation giving rise to the sustained plasma levels observed after injection of the D-Ser1-substituted octadecapeptide but not after injection of the tetracosapeptide. Although initially the kidneys did not clear such large amounts of peptide as did muscle and skin they played an important role by continuously and, on the basis of existing evidence, irreversibly clearing the peptides and peptide fragments from the circulation and degrading them.

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“…High-pressure liquid chromatography (HPLC) of the unlabelled peptide was carried out using a Du Pont model 850 HPLC system with a spectrophotometer model 852 and a column compartment model 850 in conjunction with one of the following isocratic reverse-phase systems: (A) p-Bondapak Cra, CHaCN/ 50 mM H3P04, Amino acid analysis of the unlabelled peptide was performed as described in [l] and of the tritiated peptide as in [6].…”

Section: Methodsmentioning

confidence: 99%