Synthesis and Biological Evaluation of 2,3,5-Substituted [1,2,4]Thiadiazoles as Allosteric Modulators of Adenosine Receptors

• Published in: Journal of medicinal chemistry 2004-01, Vol.47 (3), p.663-672
• Main Authors: van den Nieuwendijk, Adrianus M. C. H, Pietra, Daniele, Heitman, Laura, Göblyös, Anikó, IJzerman, Adriaan P
• Format: Article
• Language: English
• Subjects: Adenosine A1 Receptor Agonists; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Allosteric Regulation; Animals; Binding, Competitive; Biological and medical sciences; Cell Line; Cricetinae; Humans; Kinetics; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Radioligand Assay; Receptor, Adenosine A1 - drug effects; Receptor, Adenosine A2A - drug effects; Receptor, Adenosine A3 - drug effects; Receptors, Purinergic P1 - drug effects; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030863d

A number of 2,3,5-substituted [1,2,4]thiadiazole analogues of SCH-202676 (N-(2,3-diphenyl[1,2,4]thiadiazole-5(2H)-ylidene)methanamine, 7a) were synthesized and tested as potential allosteric modulators of adenosine receptors. All compounds were capable of displacing the binding of the radiolabeled agonist [3H]CCPA to human A1 adenosine receptors, whereas modest and varying effects were observed on the binding of [3H]DPCPX, a radiolabeled antagonist for this receptor subtype. Four compounds, 7a (SCH-202676), 7k (LUF5792), 7l (LUF5794), and 8e (LUF5789), were selected for more detailed characterization. They all proved allosteric inhibitors of agonist binding, with 7k being most potent, whereas their effects on antagonist binding were more ambiguous. Subsequently, experiments were done on human adenosine A2A and A3 receptors. Compounds 7a and 7l displayed peculiar displacement characteristics of both radiolabeled agonist and antagonist binding to A2A receptors, whereas 7a showed some activity on A3 receptors.