TY  - JOUR
AU  - Renk, Dana R.
AU  - Skraban, Marcel
AU  - Bier, Dirk
AU  - Schulze, Annette
AU  - Wabbals, Erika
AU  - Wedekind, Franziska
AU  - Neumaier, Felix
AU  - Neumaier, Bernd
AU  - Holschbach, Marcus
TI  - Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A2A receptor ligands
JO  - European journal of medicinal chemistry
VL  - 214
SN  - 0223-5234
CY  - Amsterdam [u.a.]
PB  - Elsevier71544
M1  - FZJ-2021-01420
SP  - 113214
PY  - 2021
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 33548636
UR  - <Go to ISI:>//WOS:000629633800015
DO  - DOI:10.1016/j.ejmech.2021.113214
UR  - https://juser.fz-juelich.de/record/891313
ER  -