title: Synthesis and biological evaluation of 2,3,5-substituted [1,2,4]thiadiazoles as allosteric modulators of adenosine receptors.
abstract: 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 [(3)H]CCPA to human A(1) adenosine receptors, whereas modest and varying effects were observed on the binding of [(3)H]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 A(2A) and A(3) receptors. Compounds 7a and 7l displayed peculiar displacement characteristics of both radiolabeled agonist and antagonist binding to A(2A) receptors, whereas 7a showed some activity on A(3) receptors.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, P.O. Box 9502, 2300RA Leiden, The Netherlands.
authors.forename: Adrianus M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.forename: Daniele
authors.initials: D
authors.lastname: Pietra
authors.forename: Laura
authors.initials: L
authors.lastname: Heitman
authors.forename: Anikó
authors.initials: A
authors.lastname: Göblyös
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007700:Kinetics; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D043682:Receptor, Adenosine A1 / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D043684:Receptor, Adenosine A3 / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C482797:5-N-methylimino-2-(3-methylphenyl)-3-phenyl-2H-(1,2,4)-thiadiazole; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; C418425:SCH-202676; D013830:Thiadiazoles; D013844:Thiazoles