Adenosine receptor prodrugs: synthesis and biological activity of derivatives of potent, A1-selective agonists.
5'-Ester derivatives of the potent adenosine agonists N6-[4-[[[[4-[[[(2-acetylaminoethyl)amino]carbonyl]methyl] anilino]carbonyl]methyl]phenyl]adenosine (N-AcADAC; 1) and N6-cyclopentyladenosine (CPA; 2) were prepared as prodrugs. Both alkyl esters or carbonates (designed to enter the brain by virtue of increased lipophilicity) and 1,4-dihydro-1-methyl-3-[(pyridinylcarbonyl)oxy]esters designed to concentrate in the brain by virtue of a redox delivery system were synthesized. In the 5'-blocked form, the adenosine agonists displayed highly diminished affinity for rat brain A1-adenosine receptors in binding assays. The dihydropyridine prodrug 29 was active in an assay of locomotor depression in mice, in which adenosine agonists are highly depressant. The behavior depression was not reversible by peripheral administration of a non-central nervous system active adenosine antagonist. In an assay of the peripheral action of adenosine (i.e., the inhibition of lipolysis in rats), the parent compounds were highly potent and the dihydropyridine prodrug was much less potent.
Maillard
M C
MC
Hershey Medical Center, Pennsylvania State University, Hershey.
Nikodijević
O
O
LaNoue
K F
KF
Berkich
D
D
Ji
X D
XD
Bartus
R
R
Jacobson
K A
KA
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D005990:Glycerol / Q000097:blood; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D013329:Structure-Activity Relationship
D011355:Prodrugs; D018047:Receptors, Purinergic P1; D000241:Adenosine; D005990:Glycerol