Allosteric modulation of the adenosine A1 receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding

Article abstract of DOI:10.1021/jm991051d

Novel allosteric enhancers of agonist binding to the rat adenosine A₁ receptor are described. The lead compound for the new series was PD 81,723 ((2-amino-4,5-dimethyl-3-thienyl)[3-(trifluoromethyl)phenyl]methanone), a compound previously reported by Bruns and co-workers (Mol. Pharmacol. 1990, 38, 950-958). The 4,5-dimethyl group and the benzoyl moiety were targets for further modifications, leading to series of 4,5-dialkyl (12a-g), of tetrahydrobenzo (12h-u), and of tetrahydropyridine (13a-g) derivatives. A number of compounds, in particular 12b, 12e, 12j, 12n, and 12u, proved superior to PD 81,723. Their EC50 values for enhancing the binding of the adenosine A₁ receptor agonist N⁶-cyclopentyladenosine to the receptor were lower, and/or their antagonistic activity on the adenosine A₁ receptor was shown to be diminished.