Conjugable A(3) adenosine receptor antagonists for the development of functionalized ligands and their use in fluorescent probes
| Autor: | Zhan-Guo Gao, Kenneth A. Jacobson, Enrico Margiotta, Stephanie Federico, Stefano Moro, Giampiero Spalluto, Eszter Kozma |
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| Přispěvatelé: | Federico, S., Margiotta, E., Moro, S., Kozma, E., Gao, Z. -G., Jacobson, K. A., Spalluto, G. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Molecular model
Adenosine receptors Fluorescent ligands G protein-coupled receptor Molecular modeling Molecular probes Conjugated system Molecular Dynamics Simulation Ligands 01 natural sciences Article Dose-Response Relationship 03 medical and health sciences Structure-Activity Relationship Fluorescent ligand Drug Discovery Moiety Humans 030304 developmental biology Fluorescent Dyes Pharmacology 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Receptor Adenosine A3 Adenosine receptor General Medicine Purinergic P1 Receptor Antagonists Combinatorial chemistry 0104 chemical sciences Biological target Adenosine A3 Drug delivery Click chemistry Drug Receptor |
| Zdroj: | Eur J Med Chem |
| Popis: | 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(3) 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(3)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(3)AR receptor. As expected, conjugable compounds showed good affinity towards the hA(3)AR. In order to prove their potential in the development of hA(3)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(2A)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. |
| Databáze: | OpenAIRE |
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