Agonist derived molecular probes for A2 adenosine receptors

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Abstract
The adenosine agonist 2‐(4‐(2‐carboxyethyl)phenylethylamino)‐5′‐N‐ethylcarboxamidoadenosine (CGS21680) was recently reported to be selective for the A2 adenosine receptor subtype, which mediates its hypotensive action. To investigate structure/activity relationships at a distal site, CGS21680 was derivatized using a functionalized congener approach. The carboxylic group of CGS21680 has been esterified to form a methyl ester, which was then treated with ethylenediamine to produce an amine congener. The amine congener was an intermediate for acylation reactions, in which the reactive acyl species contained a reported group, or the precursor for such. For radioiodination, derivatives of p‐hydroxyphenylpropionic, 2‐thiophenylacetic, and p‐aminophenylacetic acids were prepared. The latter derivative (PAPA‐APEC) was iodinated electrophilically using [125I]iodide resulting in a radioligand which was used for studies of competition of binding to striatal A2 adenosine receptors in bovine brain. A biotin conjugate and an aryl sulfonate were at least 350‐fold selective for A2 receptors. For spectroscopic detection, a derivative of the stable free radical tetramethyl‐1‐piperidinyloxy (TEMPO) was prepared. For irreversible inhibition of receptors, meta‐ and para‐phenylenediisothiocyanate groups were incorporated in the analogs. We have demonstrated that binding at A2 receptors is relatively insensitive to distal structural changes at the 2‐position, and we report high affinity molecular probes for receptor characterization by radioactive, spectroscopic and affinity lebelling methodology.

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