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

Abstract

Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, 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-[1,2,3]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.

The Distinct Role of Medium Spiny Neurons and Cholinergic Interneurons in the D2/A2AReceptor Interaction in the Striatum: Implications for Parkinson's Disease

“…1C) was recorded for 10 -15 min to obtain a baseline control. In this condition, neither 10 M quinpirole, a D 2 receptor agonist, nor 1 M ZM241385 or 10 M ST1535 (Minetti et al, 2005;Stasi et al, 2006), two A 2A receptor antagonists, bath applied alone, affected the EPSP or EPSC amplitude ( Fig. 1 A-C).…”

Synthesis and Applications of Azolylpurine and Azolylpurine Nucleoside Derivatives

“…Regioisomers were separated by flash chromatography on silica gel. [24,25] Scheme 10. Synthesis of compounds 45a-f in S N Ar reactions with azoles.…”

“…The structures of these compounds indicated that medium-sized linear alkyl chains (CH 2 ) n CH 3 (where n Ͼ 2) or bulky alkyl chains [(CH 2 ) 2 Ph] promote affinity toward the adenosine A 2A receptor; in contrast, short or branched alkyl chains are not so active toward the receptor. [24,25] Other examples of observed biological activities of purine-azole conjugates are summarized in Table 9. Table 9.…”

Adenosine A2A Receptor Antagonists and Parkinson’s Disease

“…50 A series of triazolo-9H-purines was reported as potent A 2A antagonists having modest selectivity versus A 1 ( Figure 13). 51 Compounds 45 and 46 (ST-1535) are representative examples of the series developed by Sigma Tau. ST-1535 has been characterized extensively in various animal models of PD.…”