Behavioral effects of A1- and A2-selective adenosine agonists and antagonists: evidence for synergism and antagonism.
The locomotor effects in mice of selective A1 and A2 adenosine agonists, antagonists and combinations of agonists were investigated using a computerized activity monitor. The A2-selective agonist 2-[(2-aminoethylamino)carbonylethylphenylethylamino[-5'-N- ethylcarboxamidoadenosine (APEC), an amine derivative of 2-(carboxyethylphenylethylamino)adenosine-5'-carboxamide, was a more potent locomotor depressant than its amide conjugates. The rank order of potency after i.p. injection for adenosine agonists was 5'-N-ethylcarboxamidoadenosine (NECA) (ED50, 5.8 nmol/kg) greater than APEC (ED50, 25 nmol/kg) greater than N6-cyclohexyladenosine (CHA) (ED50, 270 nmol/kg). An A1-selective, centrally acting, adenosine antagonist, 8-cyclopentyltheophylline (10 mg/kg), completely reversed the locomotor depressant effects of CHA (A1-selective) and NECA (nonselective) at doses of agonists as high as twice the ED50, and shifted the dose-response curves to the right, suggesting a primary involvement of A1 receptors. 8-cyclopentyltheophylline did not affect the depressant effects of APEC at the ED50, consistent with the A2-selectivity of APEC. The locomotor effects of APEC and CHA were completely reversed by theophylline, but not by the peripherally active 8-p-sulfophenyltheophylline, indicating central action of the adenosine agonists. The depressant effects of APEC, but not of NECA or CHA, were reversed significantly by an A2-selective adenosine receptor antagonist, 4-amino-8-chloro-1-phenyl-[1,2,4]triazol[4,3-a]quinoxaline. Low or subthreshold doses of CHA potentiated the depressant effects of APEC. A subthreshold dose of CHA did not alter the depressant effect of NECA, whereas a subthreshold dose of APEC increased the depressant effects of low doses of NECA. Thus, it appears that A1- and A2-selective adenosine agonists have separate central depressant effects, which can be potentiative.(ABSTRACT TRUNCATED AT 250 WORDS)
Nikodijević
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O
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Sarges
R
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Daly
J W
JW
Jacobson
K A
KA
D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D007274:Injections, Intraperitoneal; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D010627:Phenethylamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000187:drug effects; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D010627:Phenethylamines; D011983:Receptors, Purinergic; D014665:Vasodilator Agents; C063208:2-((2-aminoethylamino)carbonylethylphenylethylamino)-5'-N-ethylcarboxamidoadenosine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D019830:Adenosine-5'-(N-ethylcarboxamide); D013806:Theophylline; D000241:Adenosine