Molecular probes for the human adenosine receptors

Abstract

Adenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail.

Single Stabilizing Point Mutation Enables High‐Resolution Co‐Crystal Structures of the Adenosine A2A Receptor with Preladenant Conjugates

“…The tricyclic Preladenant scaffold has therefore been utilized to develop tool compounds and labeled diagnostics, e.g. positron emission tomography tracers [16] and fluorescence‐labeled derivatives [17] …”

“…positron emission tomography tracers [16] and fluorescence-labeled derivatives. [17] Although several high-resolution crystal structures of the A 2A AR were obtained, no structures in complex with Preladenant or its derivatives have been reported. Thus, the exact binding mode and interactions of this prominent and unique class of A 2A AR antagonists are still unknown.…”

Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group

“…10 This facilitates purification, isolation and crystallization of the receptor and allows for a more thorough pharmacological characterization on a molecular level. 9,11 Over the past decades, various high affinity xanthine derivatives have been developed as antagonists for the adenosine receptors. 12 In case of the A 2B AR these are mostly N 1 ,N 3 -dipropylxanthines, developed by the lab of Jacobson, 13,14 and N 1 -propylxanthines, developed by the lab of Müller.…”

Eine einzige stabilisierende Punktmutation ermöglicht hochaufgelöste Co‐Kristallstrukturen des Adenosin‐A2A‐Rezeptors mit Preladenant‐Konjugaten

“…B. für die Positronemissionstomographie, [16] sowie von Fluoreszenz-markierten Derivaten genutzt worden. [17] Auch wenn mehrere hochaufgelöste Kristallstrukturen des A 2A ARs erhalten werden konnten, wurden bisher keine Strukturen im Komplex mit Preladenant oder seinen Derivaten publiziert. Daher sind der genaue Bindungsmodus und die Interaktionen dieser prominenten und einzigartigen Klasse von A 2A AR-Antagonisten nach wie vor unbekannt.…”

“…Die tricyclische Preladenant‐Struktur ist daher für die Entwicklung von Tool‐Verbindungen und markierten Diagnostika, z. B. für die Positronemissionstomographie, [16] sowie von Fluoreszenz‐markierten Derivaten genutzt worden [17] …”