Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A receptor ligands.

With the aim to obtain potent adenosine A receptor (AR) 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 A-and A receptors were determined using radioligand binding assays. K values for human AR ranged from 2.4 to 38 nM, with more than 120-fold selectivity over A receptors for all evaluated compounds except 13k which had a K of 361 nM and 18-fold selectivity. The most potent fluorine-containing derivatives 13e, 13g and 13l exhibited K values of 4.9 nM, 3.6 nM and 2.8 nM for the human AR. Interestingly, the corresponding values for rat AR were found to be four to five times higher. Their binding to AR was further confirmed by radiolabeling with F and in vitro autoradiography in rat brain slices, which showed almost exclusive striatal binding and complete displacement by the AR antagonist ZM 241385. We conclude that these compounds represent potential candidates for the visualization of the A receptor and open pathways to novel therapeutic treatments of neurodegenerative disorders or cancer.