Pyrazolo[4,3-e ][1,2,4]triazolo[1,5-c ]pyrimidines to develop functionalized ligands to target adenosine receptors: fluorescent ligands as an example

MedChemComm
Stephanie FedericoGiampiero Spalluto

Abstract

A series of adenosine receptor antagonists bearing a reactive linker was developed. Functionalization of these derivatives is useful to easily obtain multi-target ligands, receptor probes, drug delivery systems, and diagnostic or theranostic systems. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold was chosen as a pharmacophore for the adenosine receptors. It was substituted at the 5 position with reactive linkers of different lengths. Then, these compounds were used to synthesise probes for the adenosine receptors by functionalization with a fluorescent moiety. Both series of compounds were evaluated for their binding at the four adenosine receptor subtypes. Different affinity and selectivity profiles were observed towards hA1, hA2A and hA3 adenosine receptors. In particular, fluorescent compounds behave as dual hA2A/hA3 ligands. Computational studies suggested different binding modes for developed compounds at the three receptors. Both molecular docking and supervised molecular dynamics (SuMD) simulations confirmed that the preferred binding mode at the single receptor was driven by the substitution present at the 5 position. Obtained results rationalized the compounds' binding profile at the adenosine receptors a...Continue Reading

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Oct 14, 2005·Journal of Medicinal Chemistry·Richard Morphy, Zoran Rankovic
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jan 7, 2006·Bioinformatics·Mikhail A LomizeHenry I Mosberg
Jan 31, 2006·Angewandte Chemie·Rainer Haag, Felix Kratz
Nov 28, 2006·Current Opinion in Biotechnology·David E Sosnovik, Ralph Weissleder
May 12, 2009·Trends in Immunology·György HaskóPál Pacher
Jul 2, 2010·Kidney International·Berthold Hocher
Mar 29, 2013·Nature Reviews. Drug Discovery·Jiang-Fan ChenBertil B Fredholm
Jan 25, 2014·Journal of Chemical Information and Modeling·Davide Sabbadin, Stefano Moro
Apr 19, 2015·Neuropharmacology·Francisco CiruelaKenneth A Jacobson
May 17, 2015·Neuropharmacology·Leigh A StoddartStephen J Hill
Oct 27, 2016·Neuroscience·J Sawynok
Nov 6, 2015·Trends in Pharmacological Sciences·Antonella CiancettaStefano Moro
Jun 9, 2009·Journal of Chemical Theory and Computation·M J HarveyG De Fabritiis
Mar 29, 2016·Journal of Chemical Information and Modeling·Alberto CuzzolinStefano Moro
Feb 25, 2017·Cell·Alisa GlukhovaArthur Christopoulos
Sep 13, 2017·Chemical Reviews·Madduri Srinivasarao, Philip S Low
Apr 26, 2018·Mini Reviews in Medicinal Chemistry·Barbara CacciariStephanie Federico
May 13, 2018·Purinergic Signalling·Sonja HinzChrista E Müller
Aug 8, 2018·Brain Research Bulletin·Bushra NabiJaved Ali
Nov 6, 2018·Pharmaceutics·Milica MarkovicArik Dahan

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Citations

Nov 16, 2019·Pharmaceuticals·Stephanie FedericoGiampiero Spalluto
May 29, 2021·RSC Medicinal Chemistry·Stephanie FedericoGiampiero Spalluto

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Methods Mentioned

BETA
NMR

Software Mentioned

VMD
MOE
SuMD
builder
Paramchem
ACEMD
UCSF Chimera
Linux workstation
RDKit
Gaussian

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