Agonist activity of 2- and 5'-substituted adenosine analogs and their N6-cycloalkyl derivatives at A1- and A2-adenosine receptors coupled to adenylate cyclase.
The activity of N6-cycloalkyl derivatives of adenosine, 2-chloroadenosine, 5'-chloroadenosine and N-ethylcarboximidoadenosine (NECA) and of 2-fluoroadenosine and 5-methylthioadenosines were compared at the A1-adenosine receptor inhibitory to adenylate cyclase in rat fat cell membranes and at the A2A-adenosine receptors stimulatory to adenylate cyclase in rat PC12 cell membranes. The N6-cycloalkyl derivatives in all cases were more potent (4- to 23-fold) than the parent compound at the A1 receptor, and were less potent (1.6- to 11-fold) than the parent compound at the A2A receptor. N6-Cyclopentyl-5'-chloroadenosine was the most selective agonist (900-fold) for the A1 receptor, while 2-fluoroadenosine was the only agonist with some selectivity (4.8-fold) for the A2A receptor. 5'-Methylthioadenosine was a weak agonist at both adenosine receptors. A 2-fluoro derivative of 5'-methylthioadenosine was somewhat more potent. Affinities of these analogs for inhibition of binding of radioligands to rat brain A1 and A2A receptors are presented.
Daly
J W
JW
Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Padgett
W L
WL
D000241:Adenosine / Q000031:analogs & derivatives*; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016716:PC12 Cells / Q000187:drug effects; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D011983:Receptors, Purinergic; D000262:Adenylyl Cyclases; D000241:Adenosine