Structure-activity relationships have been investigated through substitutions at the 9-position of the 2-amino-6-(2-furanyl) purine (5) to identify novel and selective A(2A) adenosine receptor antagonists. Several potent and selective antagonists were identified. In particular, compounds 20, 25, and 26 show very high affinity with excellent selectivity.
"Xanthine and non-xanthine compounds possessed strong binding affinity with A 2A R and high selectivity versus A 1 receptor. However, xanthine compounds such as KW6002 were mostly unsuccessful in clinical trials  and nonxanthines such as SCH58261 suffered from lower selectivity, poor solubility and poor pharmacokinetic profile . Therefore, we directed our efforts to search for a novel compound superseding the limitations of known A 2A R antagonists. "
[Show abstract][Hide abstract] ABSTRACT: Adenosine A(2A) receptor (A(2A)R) antagonists have emerged as potential drug candidates to alleviate progression and symptoms of Parkinson's disease (PD), and reduce the dopaminergic side effects. The synthesis of novel compound 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2-(3H)-thione (BTTP) was carried out to evaluate the potential of BTTP as A(2A)R antagonist using SCH58261, a standard A(2A)R antagonist. The strong interaction of BTTP with A(2A)R (ΔG=-12.46kcal/mol and K(i)=0.6nM) in silico analysis was confirmed by radioligand receptor binding studies showing high affinity (K(i)=0.004nM) and selectivity with A(2A)R (A(2A)/A(1)=1155-fold). The effect of CGS21680 (selective A(2A)R agonist) induced cAMP concentration (0.1pmol/ml) in HEK293 cells was antagonized with BTTP (0.065pmol/ml) and SCH58261 (0.075pmol/ml). Furthermore, BTTP pre-treated (5, 10 and 20mg/kg) haloperidol-induced mice demonstrated significant attenuation in catalepsy and akinesia. BTTP induced elevation in the striatal dopamine concentration (2.90μM/mg of tissue) was comparable to SCH58261 (2.92μM/mg of tissue) at the dose of 10mg/kg. The results firmly articulate that BTTP possesses potential A(2A)R antagonist activity and can be further explored for the treatment of PD.
[Show abstract][Hide abstract] ABSTRACT: The structure–activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A2A receptor antagonism. Several compounds displayed oral activity at 3mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.
[Show abstract][Hide abstract] ABSTRACT: The synthesis of a series of N1-aryl inosine and guanosine derivatives is described. The procedure for chemoselective N1-arylation involves the mild oxidative copper(II) mediated coupling with boronic acids. This approach provides access to substituted N1-aryl purines with interesting structural characteristics and novel scaffolds for drug discovery.
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