2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and Analogues as A_(2A)Adenosine Receptor Antagonists.Design,Synthesis,and Pharmacological Characterization

摘要

Two types of adenosine receptor ligands were designed,i.e.,9H-purine and lH-imidazo[4,5-clpyridines,to obtain selective A_(2A)antagonists,and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A_1,A_(2A),A_(2B)and A_3.The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature.Three compounds(25b-d)showed an interesting affinity and selectivity for the A_(2A)subtype.One of them,i.e.,ST1535(2-n-butyl-9-methyl-8-[l,2,3]triazol-2-yl-9H-purin-6-ylamine,25b)(K_i A_(2A)=6.6 nM,K_i A_1/A_(2A)=12;K_i A_(2B)/A_(2A)=58;K_i A_3/A_(2A)> 160),was selected for in vivo study and shown to induce a dose-related increase in locomotor activity,suggestive of an A_(2A)antagonist type of activity.