RT Journal Article
SR Electronic
T1 SCH-202676: An Allosteric Modulator of Both Agonist and Antagonist Binding to G Protein-Coupled Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 30
OP 37
DO 10.1124/mol.59.1.30
VO 59
IS 1
A1 Ahmad B. Fawzi
A1 Douglas Macdonald
A1 Lawrence L. Benbow
A1 April Smith-Torhan
A1 Hongtao Zhang
A1 Blair C. Weig
A1 Ginny Ho
A1 Deen Tulshian
A1 Maurine E. Linder
A1 Michael P. Graziano
YR 2001
UL http://molpharm.aspetjournals.org/content/59/1/30.abstract
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.