Conjugable A 3 adenosine receptor antagonists for the development of functionalized ligands and their use in fluorescent probes

• Published in: European journal of medicinal chemistry Vol. 186; p. 111886
• Main Authors: Federico, Stephanie, Margiotta, Enrico, Moro, Stefano, Kozma, Eszter, Gao, Zhan-Guo, Jacobson, Kenneth A, Spalluto, Giampiero
• Format: Journal Article
• Language: English
• Published: France 15.01.2020
• Subjects: Dose-Response Relationship, Drug; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - chemistry; Fluorescent Dyes - pharmacology; Humans; Ligands; Molecular Dynamics Simulation; Molecular Structure; Purinergic P1 Receptor Antagonists - chemical synthesis; Purinergic P1 Receptor Antagonists - chemistry; Purinergic P1 Receptor Antagonists - pharmacology; Receptor, Adenosine A3 - metabolism; Structure-Activity Relationship; G protein-coupled receptor; Adenosine receptors; Molecular modeling; Molecular probes; Fluorescent ligands
• ISSN: 1768-3254

Compounds able to simultaneously bind a biological target and be conjugated to a second specific moiety are attractive tools for the development of multi-purpose ligands useful as multi-target ligands, receptor probes or drug delivery systems, with both therapeutic and diagnostic applications. The human A adenosine receptor is a G protein-coupled receptor involved in many physio-pathological conditions, e.g. cancer and inflammation, thus representing a promising research target. In this work, two series of conjugable hA AR antagonists, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus, were developed. The introduction of an aromatic ring at the 5 position of the scaffold, before (phenylacetamido moiety) or after (1,2,3-triazole obtained by click chemistry) the conjugation is aimed to increase affinity and selectivity towards the hA AR receptor. As expected, conjugable compounds showed good affinity towards the hA AR. In order to prove their potential in the development of hA AR ligands for different purposes, compounds were also functionalized with fluorescent probes. Unfortunately, conjugation decreased affinity and selectivity for the target as compared to the hA AR. Computational studies identified specific non-conserved residues of the extracellular loops which constitute a structural barrier able to discriminate between ligands, giving insights into the rational development of new highly selective ligands.