ADENOSINE RECEPTOR PRODRUGS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF DERIVATIVES OF POTENT, A(1)-SELECTIVE AGONISTS

5'-Ester derivatives of the potent adenosine agonists yl]methyl]anilin o]carbonyl]methyl]phenyl]adenosine (N-AcADAC; 1) and N-6-cyclopentylad enosine (CPA; 2) were prepared as prodrugs. Both alkyl esters or carbo nates (designed to enter the brain by virtue of increased lipophilicit y) and -dihydro-1-methyl-3-[(pyridinylcarbonyl)oxy]esters designed to concentrate in the brain by virtue of a redox delivery system were syn thesized. In the 5'-blocked form, the adenosine agonists displayed hig hly diminished affinity for rat brain A(1)-adenosine receptors in bind ing assays. The dihydropyridine prodrug 29 was active in an assay of l ocomotor depression in mice, in which adenosine agonists are highly de pressant. The behavior depression was not reversible by peripheral adm inistration of a non-central nervous system active adenosine antagonis t. In an assay of the peripheral action of adenosine (i.e., the inhibi tion of lipolysis in rats), the parent compounds were highly potent an d the dihydropyridine prodrug was much less potent.