SCH-202676: An allosteric modulator of both agonist and antagonist binding to G protein-coupled receptors.

摘要: 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). inhibited radioligand a number structurally distinct, heterologously expressed GPCRs, including the human μ-, δ-, κ-opioid, α- β-adrenergic, muscarinic M1 M2, dopaminergic D1 D2receptors, but not tyrosine kinase epidermal growth factor receptor. had no direct effect on protein activity assessed by [35S]guanosine-5′-O-(γ-thio)triphosphate purified recombinant Goα- or Gβγ-stimulated ADP-ribosylation Goα pertussis toxin. In addition, β2-adrenergic receptor in Escherichia coli, system devoid classical heterotrimeric proteins. radiolabeled α2a-adrenergic with IC50 value 0.5 μM, decreased theBmax sites slight increase KD value, agonist-induced activation The effects were reversible. Incubation plasma membranes 10 μM did alter subsequent Taken together, our data suggest that unique ability allosterically regulate GPCRs manner is selective scope presented suggests this occurs interaction structural motif common large activation/inhibition unidentified accessory regulates GPCR function.