Effects of the allosteric modulator SCH-202676 on adenosine and P2Y receptors.
The G protein-coupled receptor allosteric modulator SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5-(2H)-ylidene)methanamine), which affects a wide range of structurally unrelated G protein-coupled receptors, has highly divergent effects on purine receptors. SCH-202676 inhibited radioligand binding to human adenosine A(1), A(2A), and A(3) receptors (IC(50) = 0.5-0.8 microM) and affected dissociation kinetics, but at the human P2Y(1) nucleotide receptor it had no effect. SCH-202676 (10 microM) selectively accelerated agonist dissociation at adenosine A(3) receptors and either slowed (adenosine A(1) receptors) or accelerated (adenosine A(2A) receptors) antagonist dissociation. Thus, SCH-202676 differentially modulated A(1), A(2A), and A(3) receptors as well as agonist- and antagonist-occupied receptors.
Gao
Zhan-Guo
ZG
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892-0810, USA.
Gross
Ariel S
AS
Jacobson
Kenneth A
KA
D000494:Allosteric Regulation; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology; D001667:Binding, Competitive; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D007700:Kinetics; D011869:Radioligand Assay; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1; D013830:Thiadiazoles; D013844:Thiazoles / Q000494:pharmacology*
C546382:P2RY1 protein, human; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; C418425:SCH-202676; D013830:Thiadiazoles; D013844:Thiazoles