title: Allosteric modulation of the adenosine A(1) receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding.
abstract: Novel allosteric enhancers of agonist binding to the rat adenosine A(1) 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 EC(50) values for enhancing the binding of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine to the receptor were lower, and/or their antagonistic activity on the adenosine A(1) receptor was shown to be diminished.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, P.O. Box 9502, 2300 RA Leiden, The Netherlands. klein_p@chem.leidenuniv.nl
authors.forename: P A
authors.initials: PA
authors.lastname: van der Klein
authors.forename: A P
authors.initials: AP
authors.lastname: Kourounakis
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014970:Xanthines / Q000378:metabolism
chemical_list: D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D013876:Thiophenes; D014970:Xanthines; C075004:PD 81723; C048599:N(6)-cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine