A role for central A3-adenosine receptors. Mediation of behavioral depressant effects.
The behavioral effects of a selective A3 adenosine receptor agonist 3-IB-MECA (N6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine) in mice and the localization of radioligand binding sites in mouse brain were examined. Low levels of A3 adenosine receptors were detected in various regions of the mouse brain (hippocampus, cortex, cerebellum, striatum), using a radioiodinated, high-affinity A3-agonist radioligand [125I]AB-MECA (N6-(3-iodo-4-aminobenzyl)-5'-N-methylcarboxamidoadenosine). Scatchard analysis in the cerebellum showed that the Kd value for binding to A3 receptors was 1.39 +/- 0.04 nM with a Bmax of 14.8 +/- 2.1 fmol/mg protein. 3-IB-MECA at 0.1 mg/kg i.p. was a locomotor depressant with > 50% reduction in activity. Although selective A1 or A2a antagonists reversed locomotor depression elicited by selective A1 or A2a agonists, respectively, the behavioral depressant effects of 3-IB-MECA were unaffected. 3-IB-MECA also caused scratching in mice, which was prevented by coadministration of the histamine antagonist cyproheptadine. The demonstration of a marked behavioral effect of A3 receptor activation suggests that the A3 receptor represents a potential new therapeutic target.
Jacobson
K A
KA
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Nikodijević
O
O
Shi
D
D
Gallo-Rodriguez
C
C
Olah
M E
ME
Stiles
G L
GL
Daly
J W
JW
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology
D010627:Phenethylamines; D018047:Receptors, Purinergic P1; D014970:Xanthines; C063208:2-((2-aminoethylamino)carbonylethylphenylethylamino)-5'-N-ethylcarboxamidoadenosine; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine