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With the aim to obtain potent adenosine A_2A receptor (A_2AR) 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 A_2A receptors were determined using radioligand binding assays. K_i values for human A_2AR 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 K_i of 361 nM and 18-fold selectivity. The most potent fluorine-containing derivatives 13e, 13g and 13l exhibited …