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@ARTICLE{Renk:891313,
author = {Renk, Dana R. and Skraban, Marcel and Bier, Dirk and
Schulze, Annette and Wabbals, Erika and Wedekind, Franziska
and Neumaier, Felix and Neumaier, Bernd and Holschbach,
Marcus},
title = {{D}esign, synthesis and biological evaluation of
{T}ozadenant analogues as adenosine {A}2{A} receptor
ligands},
journal = {European journal of medicinal chemistry},
volume = {214},
issn = {0223-5234},
address = {Amsterdam [u.a.]},
publisher = {Elsevier71544},
reportid = {FZJ-2021-01420},
pages = {113214},
year = {2021},
abstract = {With the aim to obtain potent adenosine A2A receptor (A2AR)
ligands, a series of eighteen derivatives of
4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide
(SYN-115, Tozadenant) were designed and synthesized. The
target compounds were obtained by a chemical building block
principle that involved reaction of the appropriate
aminobenzothiazole phenyl carbamates with either
commercially available or readily synthesized functionalized
piperidines. Their affinity and subtype selectivity with
regard to human adenosine A1-and A2A receptors were
determined using radioligand binding assays. Ki values for
human A2AR ranged from 2.4 to 38 nM, with more than 120-fold
selectivity over A1 receptors for all evaluated compounds
except 13k which had a Ki of 361 nM and 18-fold selectivity.
The most potent fluorine-containing derivatives 13e, 13g and
13l exhibited Ki values of 4.9 nM, 3.6 nM and 2.8 nM for the
human A2AR. Interestingly, the corresponding values for rat
A2AR were found to be four to five times higher. Their
binding to A2AR was further confirmed by radiolabeling with
18F and in vitro autoradiography in rat brain slices, which
showed almost exclusive striatal binding and complete
displacement by the A2AR antagonist ZM 241385. We conclude
that these compounds represent potential candidates for the
visualization of the A2A receptor and open pathways to novel
therapeutic treatments of neurodegenerative disorders or
cancer.},
cin = {INM-5 / INM-2},
ddc = {610},
cid = {I:(DE-Juel1)INM-5-20090406 / I:(DE-Juel1)INM-2-20090406},
pnm = {525 - Decoding Brain Organization and Dysfunction
(POF4-525)},
pid = {G:(DE-HGF)POF4-525},
typ = {PUB:(DE-HGF)16},
pubmed = {33548636},
UT = {WOS:000629633800015},
doi = {10.1016/j.ejmech.2021.113214},
url = {https://juser.fz-juelich.de/record/891313},
}