SCH-202676: An allosteric modulator of both agonist and antagonist binding to G protein-coupled receptors.
A novel thiadiazole compound, SCH-202676 (N-(2,3-diphenyl-1,2, 4-thiadiazol-5-(2H)-ylidene)methanamine), has been identified as an inhibitor of both agonist and antagonist binding to G protein-coupled receptors (GPCRs). SCH-202676 inhibited radioligand binding to a number of structurally distinct, heterologously expressed GPCRs, including the human mu-, delta-, and kappa-opioid, alpha- and beta-adrenergic, muscarinic M1 and M2, and dopaminergic D1 and D2 receptors, but not to the tyrosine kinase epidermal growth factor receptor. SCH-202676 had no direct effect on G protein activity as assessed by [35S]guanosine-5'-O-(gamma-thio)triphosphate binding to purified recombinant G(oalpha)- or G(betagamma)-stimulated ADP-ribosylation of G(oalpha) by pertussis toxin. In addition, SCH-202676 inhibited antagonist binding to the beta2-adrenergic receptor expressed in Escherichia coli, a system devoid of classical heterotrimeric G proteins. SCH-202676 inhibited radiolabeled agonist and antagonist binding to the alpha2a-adrenergic receptor with an IC50 value of 0.5 microM, decreased the Bmax value of the binding sites with a slight increase in the KD value, and inhibited agonist-induced activation of the receptor. The effects of SCH-202676 were reversible. Incubation of plasma membranes with 10 microM SCH-202676 did not alter subsequent radioligand binding to the alpha2a-adrenergic receptor and the dopaminergic D1 receptor. Taken together, our data suggest that SCH-202676 has the unique ability to allosterically regulate agonist and antagonist binding to GPCRs in a manner that is both selective and reversible. The scope of the data presented suggests this occurs by direct interaction with a structural motif common to a large number of GPCRs or by activation/inhibition of an unidentified accessory protein that regulates GPCR function.
Fawzi
A B
AB
Central Nervous System/Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA. ahmad.fawzi@spcorp.com
Macdonald
D
D
Benbow
L L
LL
Smith-Torhan
A
A
Zhang
H
H
Weig
B C
BC
Ho
G
G
Tulshian
D
D
Linder
M E
ME
Graziano
M P
MP
D018663:Adrenergic Agents / Q000494:pharmacology*; D000494:Allosteric Regulation; D004926:Escherichia coli; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D011869:Radioligand Assay; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism*; D013830:Thiadiazoles; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018663:Adrenergic Agents; D011941:Receptors, Adrenergic; C418425:SCH-202676; D013830:Thiadiazoles; D013844:Thiazoles; D016244:Guanosine 5'-O-(3-Thiotriphosphate)