A possible heterogeneity of adenosine A1 receptors in brain was evaluated by comparing drug specificity, regional distribution, and temperature influences on 3H-labeled ligand binding in several mammalian species. Adenosine receptors were labeled with the agonists [3H] N6-cyclohexyladenosine ([3H]CHA) and [3H]N6-phenylisopropyladenosine ([3H]PIA) or the antagonist [3H]1,3-diethyl-8-phenylxanthine ([3H]DPX). The binding properties of adenosine analogues are similar in the species studied. In all cases, the N6-substituted adenosine analogues have nanomolar affinity for [3H]CHA binding sites with a marked stereoselectivity for the isomers of PIA. The xanthine derivative DPX manifests considerable differences in affinity for [3H]CHA-labeled A1 receptors of different species. DPX shows highest affinity for A1 receptors in calf brain and lowest affinity for A1 receptors in guinea pig and human brain. [3H]DPX labels adenosine A1 receptors in calf, rat, and rabbit cerebral cortical brain membranes. By contrast, very little specific [3H]DPX binding is detected in human and guinea pig brain, and the limited level of binding is inhibited poorly by PIA or xanthines. The failure of [3H]DPX to label adenosine A1 receptors in human and guinea pig cortex may be related to the very low affinity of DPX for A1 receptors in these species as labeled by [3H]CHA. Temperature variations affect agonist and antagonist binding differentially. Adenosine derivatives have higher affinities for A1 receptors at higher temperatures, whereas xanthine analogues have higher affinities at lower temperatures. Similar temperature effects on A1 receptor binding occur in all species examined. Temperature effects can account for the differences in drug affinities at [3H]agonist- and [3H]antagonist-labeled sites. Temperature effects cannot account for the failure of [3H]DPX to label A1 receptors in guinea pig and human brain. Our thermodynamic analysis of temperature influences on A1 receptor binding indicates that agonist binding is entropy-driven.

Original languageEnglish
Pages (from-to)250-257
Number of pages8
JournalMolecular pharmacology
Issue number2
StatePublished - 1982


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