Allosteric modulation of the adenosine A(1) receptor. Synthesis and biological evaluation of novel 2-amino-3-benzoylthiophenes as allosteric enhancers of agonist binding

• Published in: Journal of medicinal chemistry Vol. 42; no. 18; pp. 3629 - 3635
• Main Authors: van der Klein, PAM, Kourounakis, AP, IJzerman, AP
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 09.09.1999
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Allosteric Regulation - drug effects; Animals; Binding, Competitive; Brain - metabolism; Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Science & Technology; Thiophenes - chemical synthesis; Thiophenes - pharmacology; Xanthines - metabolism; RAT-BRAIN; AFFINITY; ADENOSINE-A1-RECEPTOR BINDING; PD-81,723
• ISSN: 0022-2623
• DOI: 10.1021/jm991051d

Novel allosteric enhancers of agonist binding to the rat adenosine Al 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 Al receptor agonist N-6-cyclopentyladenosine to the receptor were lower, and/or their antagonistic activity on the adenosine Al receptor was shown to be diminished.