title: 2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists.
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.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Gemma N
authors.initials: GN
authors.lastname: Ferguson
authors.forename: Celine
authors.initials: C
authors.lastname: Valant
authors.forename: James
authors.initials: J
authors.lastname: Horne
authors.forename: Heidi
authors.initials: H
authors.lastname: Figler
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Flynn
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: David K
authors.initials: DK
authors.lastname: Chalmers
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000737:chemistry; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D011724:Pyridazines; D043682:Receptor, Adenosine A1; D054852:Small Molecule Libraries; D013876:Thiophenes
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