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J Med Chem. 2008 Oct 9;51(19):6165-72. doi: 10.1021/jm800557d. Epub 2008 Sep 5.

2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists.

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  • 1Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.


A pharmacophore-based screen identified 32 compounds including ethyl 5-amino-3-(4- tert-butylphenyl)-4-oxo-3,4-dihydrothieno[3,4- d]pyridazine-1-carboxylate ( 8) as a new allosteric modulator of the adenosine A1 receptor (A1AR). On the basis of this lead, various derivatives were prepared and evaluated for activity at the human A 1AR. A number of the test compounds allosterically stabilized agonist-receptor-G protein ternary complexes in dissociation kinetic assays, but were found to be more potent as antagonists in subsequent functional assays of ERK1/2 phosphorylation. Additional experiments on the most potent antagonist, 13b, investigating A1AR-mediated [(35)S]GTPgammaS binding and [(3)H]CCPA equilibrium binding confirmed its antagonistic mode of action and also identified inverse agonism. This study has thus identified a new class of A1AR antagonists that can also recognize the receptor's allosteric site with lower potency.

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