1. 2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists.
- Author
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Ferguson GN, Valant C, Horne J, Figler H, Flynn BL, Linden J, Chalmers DK, Sexton PM, Christopoulos A, and Scammells PJ
- Subjects
- Allosteric Regulation drug effects, Allosteric Site drug effects, Dose-Response Relationship, Drug, Humans, Kinetics, Molecular Structure, Pyridazines chemical synthesis, Pyridazines chemistry, Receptor, Adenosine A1 chemistry, Small Molecule Libraries, Stereoisomerism, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes chemistry, Adenosine A1 Receptor Agonists, Adenosine A1 Receptor Antagonists, Pyridazines pharmacology, Thiophenes pharmacology
- Abstract
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.
- Published
- 2008
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