Effects of 5′‐Amido Analogues of Adenosine 3′: 5′‐Monophosphate and Adenosine 3′: 5′‐Monophosphothioate on Protein Kinase, Binding Protein and Phosphodiesterases

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Abstract
The biological effects of 5′‐amido analogues of adenosine 3′:5′‐monophosphate (cAMP) and monophosphothioate, with and without N‐substituents, were investigated.The unsubstituted amino analogues stimulated the cAMP‐dependent protein kinase from bovine muscle while N‐substitution prevented this effect. Some of the N‐alkyl derivatives, however, inhibited the protein kinase activity. Only adenosine 5′‐amido 3′:5′‐monophosphate was found to compete for the binding of [3H]cAMP to cAMP binding protein from bovine muscle.Phosphodiesterases from bovine heart and rabbit brain hydrolyzed 5′‐amido‐adenosine 3′: 5′‐monophosphate, but only the former hydrolyzed the corresponding phosphothioate. The heart diesterase was inhibited competitively by N‐substituted derivatives of 5′‐amido‐adenosine 3′: 5′‐monophosphate and 5′‐amido‐adenosine 3′: 5′‐monophosphothioate, but 5′‐N‐n‐octyl‐amino‐adenosine 3′:5′‐monophosphate did not inhibit any of the brain diesterases tested.Results suggest that steric and electronic requirements of the cyclophosphate ring determine the catalytic effects of the cAMP on protein kinase, while alteration in other regions of the molecule exercise an appreciably smaller effect and largely affect binding parameters. Phosphodiesterases show similar requirements for binding and reactivity.

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