A new class of compounds, peptide derivatives of adenosine 5'-carboxylic acid, includes inhibitors of ATP receptor-mediated responses.
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.
Uri
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Department of Neurochemistry & Neurotoxicology, Stockholm University, Sweden.
Järlebark
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L
von Kügelgen
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I
Schönberg
T
T
Undén
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Heilbronn
E
E
D000241:Adenosine / Q000031:analogs & derivatives*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D058914:Purinergic Antagonists; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014649:Vas Deferens / Q000187:drug effects
D002264:Carboxylic Acids; D010455:Peptides; D058914:Purinergic Antagonists; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D000241:Adenosine; D002118:Calcium