Abstract
Adenosine A2A receptors seem to exist in typical (more in striatum) and atypical (more in hippocampus and cortex) subtypes. In the present study, we investigated the affinity of two adenosine A2A receptor antagonists, ST1535 [2 butyl -9-methyl-8-(2H-1,2,3-triazol 2-yl)-9H-purin-6-xylamine] and KW6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6,dione] to the “typical” and “atypical” A2A binding sites. Affinity was determined by radioligand competition experiments in membranes from rat striatum and hippocampus. Displacement of the adenosine analog [3H]CGS21680 [2-p-(2-carboxyethyl)phenethyl-amino-5’-N-ethylcarbox-amidoadenosine] was evaluated in the absence or in the presence of either CSC [8-(3-chlorostyryl)-caffeine], an adenosine A2A antagonist that pharmacologically isolates atypical binding sites, or DPCPX (8-cyclopentyl-1,3-dipropylxanthine), an adenosine A1 receptor antagonist that pharmacologically isolates typical binding site. ZM241385 [84-(2-[7-amino-2-(2-furyl) [1,2,4]-triazol[2,3-a][1,3,5]triazin-5-yl amino]ethyl) phenol)] and SCH58261 [(5-amino-7-(β-phenylethyl)-2-(8-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine], two other adenosine A2A receptor antagonists, which were reported to differently bind to atypical and typical A2A receptors, were used as reference compounds. ST1535, KW6002, ZM241385 and SCH58261 displaced [3H]CGS21680 with higher affinity in striatum than in hippocampus. In hippocampus, no typical adenosine A2A binding was detected, and ST1535 was the only compound that occupied atypical A2A adenosine receptors. Present data are explained in terms of heteromeric association among adenosine A2A, A2B and A1 receptors, rather than with the presence of atypical A2A receptor subtype.
Highlights
Adenosine represents an endogenous inhibitory modulator widely distributed in the central nervous system, exerting its physiological actions through activation of four structurally distinct surface receptors (A1, A2A, A2B and A3), all of which represent attractive targets for several human diseases (Fredholm et al, 2001; Sebastião and Ribeiro, 2009)
As repeatedly shown, using different methods, adenosine A2A receptors are highly enriched in caudate putamen, nucleus accumbens and tuberculum olfactorium, and expression levels elsewhere are lower (Jarvis and Williams, 1989; Dixon et al, 1996)
It seems conceivable that differences in affinity values might not be due to different number of adenosine A2A receptors in the two tissues, since the ratio between the affinity values in hippocampus and striatum was not a constant but variable among the different compounds we used
Summary
Adenosine represents an endogenous inhibitory modulator widely distributed in the central nervous system, exerting its physiological actions through activation of four structurally distinct surface receptors (A1, A2A, A2B and A3), all of which represent attractive targets for several human diseases (Fredholm et al, 2001; Sebastião and Ribeiro, 2009). The second high-affinity binding site predominates in the cortex and hippocampus, and has binding characteristics intermediary between those of A1 and A2A receptors (Wan et al, 1990; Johansson et al, 1993; Kirk and Richardson, 1995; Cunha et al., 1996). In the hippocampus and cortex, but not in the striatum, most of the [3H]CGS21680 binding was displaced by DPCPX at low nanomolar concentrations (Cunha et al, 1996, 1997) This distinct pharmacological affinity profile, even though the high selectivity of [3H]CGS21680 for A2A receptors, has raised reasonable doubts as whether these atypical binding sites might represent A2A receptors
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