2-Aminopyrimidines as dual adenosine A1/A2A antagonists

• 2-Aminopyrimidines were synthesised and screened for dual adenosine A1 and A2A receptor affinity.
• Compound 8m was the most potent compound with A2A and A1Ki values of 6.34 nM and 9.54 nM respectively.
• Amide derivatives (8k and 8m) exhibited in vivo activity in the haloperidol induced catalepsy assay in rats.

In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A1 and A2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A2AKi value of 6.34 nM and an A1Ki value of 9.54 nM. The effect of selected compounds on the viability of cultured cells was assessed and preliminary results indicate low cytotoxicity. In vivo efficacy at A2A receptors was illustrated for compounds 8k and 8m since these compounds attenuated haloperidol-induced catalepsy in rats. A molecular docking study revealed that the interactions between the synthesised compounds and the adenosine A2A binding site most likely involve Phe168 and Asn253, interactions which are similar for structurally related adenosine A2A receptor antagonists.

Figure optionsDownload as PowerPoint slide