A new class of compounds, peptide derivatives of adenosine 5'-carboxylic acid, includes inhibitors of ATP receptor-mediated responses.

Abstract

A new type of ligand for the study of P2-purinergic receptor subtypes was synthesized by combining and modifying conventional nucleoside chemistry with Fmoc solid phase peptide synthesis techniques. The tri- and tetra-aspartic acid derivatives of adenosine-5'-carboxylic acid (AdoCAsp3 and AdoCAsp4) were found to act as weak agonists at P2-purinergic receptors, (activated by ATP and UTP respectively) present on C6 glioma cells. AdoCAsp4 induced inositol 1,4,5-trisphosphate formation in the C6 cells with an EC50 of 73 microM. In addition, AdoCAsp4 was found to inhibit (IC50 approximately 80 microM) ATP-induced cytosolic [Ca2+] transients in these glioma cells. The glycine derivative, AdoCGly, increased evoked release of noradrenaline from mouse vas deferens slices, probably due to the blockade of presynaptic P2-autoreceptors. The possibility that aspartic, glutamic or gamma-carboxyglutamic residues may be used to replace phosphate groups on an ATP receptor ligand, opens up new ways in ligand design.

• Authors: A Uri, L Järlebark, I von Kügelgen, T Schönberg, A Undén, E Heilbronn
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 2 Issue 10 Pg. 1099-105 (Oct 1994) ISSN: 0968-0896 [Print] England
• PMID: 7773627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carboxylic Acids
• Peptides
• Purinergic Antagonists
• Inositol 1,4,5-Trisphosphate
• Adenosine Triphosphate
• Adenosine
• Calcium

Topics

• Adenosine (analogs & derivatives)
• Adenosine Triphosphate (pharmacology)
• Animals
• Calcium (antagonists & inhibitors, metabolism)
• Carboxylic Acids (chemistry, pharmacology)
• Cytosol (metabolism)
• Inositol 1,4,5-Trisphosphate (biosynthesis)
• Male
• Mice
• Peptides (chemistry, pharmacology)
• Purinergic Antagonists
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Vas Deferens (drug effects)