By G. Hasko, et al.,
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Extra info for Adenosine Receptors - Theraputic Aspects
65 nM), was developed from the SAR study of a nonselective AR antagonist, CGS15943 59, with diverse derivatization at the exocyclic N5 position. 4 TRIAZOLOQUINOXALINES The SAR study of triazoloquinoxaline derivatives showed that the substitutions at the p-position of the phenyl ring were critical either in the probing A3AR affinity or selectivity, because of the different hydrogen-bonding interactions and steric effects in this region of the binding pocket of each receptor subtype. 60 nM and more than 16,600-fold selectivity in comparison to A1 and A2AARs.
33 Species differences in A3AR affinity that are present for agonists are especially pronounced for A3AR antagonists. 35 At the sheep and human A3ARs, the xanthines displayed intermediate affinity (typically 100 nM for 8-phenylxanthine analogs). A marked species dependence of antagonist affinity is present at the A3AR, to a greater degree than at other ARs. 34,35 Thus, the search for A3 antagonists turned toward more novel heterocyclic systems. The screening of diverse chemical libraries resulted in the identification of new “hits” for high-affinity antagonism at the human A3AR, including the following: 1.
G. , Structural determinants of A3 adenosine receptor activation: nucleoside ligands at the agonist/antagonist boundary, J. Med. , 45, 4471, 2002. 15. G. , Novel N6-(substituted-phenylcarbamoyl)adenosine-5′-uronamides as potent agonists for A3 adenosine receptors, J. Med. , 39, 802, 1996. 16. W. , New, non-adenosine, high-potency agonists for the human adenosine A2B receptor with an improved selectivity profile compared to the reference agonist N-ethylcarboxamidoadenosine, J. Med. , 47, 3707, 2004.
Adenosine Receptors - Theraputic Aspects by G. Hasko, et al.,
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