RT Journal Article
T1 Exploring Non-orthosteric Interactions with a Series of Potent and Selective A3 Antagonists
A1 Miranda Pastoriza, Darío
A1 Bernárdez Alfaya, Rodrigo
A1 Azuaje Guerrero, Jhonny Alberto
A1 Prieto Díaz, Rubén
A1 Majellaro, Maria
A1 Tamhankar, Ashish V.
A1 Koenekoop, Lucien
A1 González García, Alejandro
A1 Gioé Gallo, Claudia
A1 Mallo-Abreu, Ana
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
A1 García Rey, Aitor
A1 García Mera, Xerardo
A1 Gutiérrez de Terán, Hugo
A1 Sotelo Pérez, Eddy
K1 A3 Adenosine receptors
K1 Adenosine antagonists
K1 Pyrimidines
K1 Ugi reaction
K1 Multicomponent reactions
AB A library of potent and highly A3AR selective pyrimidine-based compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes
PB ACS Publications
SN 1948-5875
YR 2022
FD 2022
LK http://hdl.handle.net/10347/29225
UL http://hdl.handle.net/10347/29225
LA eng
NO ACS Med. Chem. Lett. 2022, 13, 2, 243–249
NO This work has received financial support from the Consellería de Cultura, Educación e Ordenación Universitaria [Galician Government (grant: ED431B 2020/43)], the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03), the European Union (European Regional Development Fund - ERDF), the Swedish Research Council (grant: 521-2014-2118), and the Swedish strategic research program eSSENCE. The computational studies were conducted with the resources available from the Swedish National Infrastructure for Computing (SNIC). The project was carried out within the framework of the collaborative EU COST action ERNEST (CA18133)
DS Minerva
RD 28 abr 2026