Functionalized congeners of adenosine: preparation of analogues with high affinity for A1-adenosine receptors

Abstract

A series of functionalized congeners of adenosine based on N6-phenyladenosine, a potent A1-adenosine receptor against, was synthesized. Derivatives of the various congeners should be useful as receptor and histochemical probes and for the preparation of radioligands and affinity columns or as targeted drugs. N6-[4-(Carboxymethyl)phenyl]adenosine served as the starting point for synthesis of the methyl ester, the methyl amide, the ethyl glycinate, and various substituted anilides. One of the latter, N6-[4-[[[4-(carbomethoxymethyl)anilino]carbonyl]methyl]phenyl] adenosine, served as the starting point for the synthesis of another series of congeners including the methyl amide, the hydrazide, and the aminoethyl amide. The terminal amino function of the last congener was acylated to provide further analogues. The various congeners were potent competitive antagonists of binding of N6-[3H]cyclohexyladenosine to A1-adenosine receptors in rat cerebral cortical membranes. The affinity of the congener for the A1 receptor was highly dependent on the nature of the spacer group and the terminal moiety with Ki values ranging 1-100 nM. A biotinylated analogue had a Ki value of 11 nM. A conjugate derived from the Bolton-Hunter reagent had a Ki value of 4.5 nM. The most potent congener contained a terminal [(aminoethyl)amino]carbonyl function and had a Ki value of less than 1 nM.

Scheme I

Synthesis of a Carboxylic Acid Congener of Adenosine and Amide Derivatives

Scheme II

Synthesis of an Amino Congener of Adenosine and Various Amide Derivatives