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2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2008 Oct 09; Vol. 51 (19), pp. 6165-72. Date of Electronic Publication: 2008 Sep 05. - Publication Year :
- 2008
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 51
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18771255
- Full Text :
- https://doi.org/10.1021/jm800557d