PT  - JOURNAL ARTICLE
AU  - Fawzi, Ahmad B.
AU  - Macdonald, Douglas
AU  - Benbow, Lawrence L.
AU  - Smith-Torhan, April
AU  - Zhang, Hongtao
AU  - Weig, Blair C.
AU  - Ho, Ginny
AU  - Tulshian, Deen
AU  - Linder, Maurine E.
AU  - Graziano, Michael P.
TI  - SCH-202676: An Allosteric Modulator of Both Agonist and Antagonist Binding to G Protein-Coupled Receptors
AID  - 10.1124/mol.59.1.30
DP  - 2001 Jan 01
TA  - Molecular Pharmacology
PG  - 30--37
VI  - 59
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/59/1/30.short
4100  - http://molpharm.aspetjournals.org/content/59/1/30.full
SO  - Mol Pharmacol2001 Jan 01; 59
AB  - 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 μ-, δ-, and κ-opioid, α- and β-adrenergic, muscarinic M1 and M2, and dopaminergic D1 and D2receptors, 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-(γ-thio)triphosphate binding to purified recombinant Goα- or Gβ γ-stimulated ADP-ribosylation of Goα by pertussis toxin. In addition, SCH-202676 inhibited antagonist binding to the β2-adrenergic receptor expressed in Escherichia coli, a system devoid of classical heterotrimeric G proteins. SCH-202676 inhibited radiolabeled agonist and antagonist binding to the α2a-adrenergic receptor with an IC50 value of 0.5 μM, decreased theB max value of the binding sites with a slight increase in the K D value, and inhibited agonist-induced activation of the receptor. The effects of SCH-202676 were reversible. Incubation of plasma membranes with 10 μM SCH-202676 did not alter subsequent radioligand binding to the α2a-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.