Allosteric modulation of the adenosine A(1) receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding.
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.
van der Klein
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PA
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, P.O. Box 9502, 2300 RA Leiden, The Netherlands. klein_p@chem.leidenuniv.nl
Kourounakis
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AP
IJzerman
A P
AP
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
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