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Molecular Pharmacology

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Research ArticleArticle

SCH-202676: An Allosteric Modulator of Both Agonist and Antagonist Binding to G Protein-Coupled Receptors

Ahmad B. Fawzi, Douglas Macdonald, Lawrence L. Benbow, April Smith-Torhan, Hongtao Zhang, Blair C. Weig, Ginny Ho, Deen Tulshian, Maurine E. Linder and Michael P. Graziano
Molecular Pharmacology January 2001, 59 (1) 30-37; DOI: https://doi.org/10.1124/mol.59.1.30
Ahmad B. Fawzi
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Douglas Macdonald
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Lawrence L. Benbow
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April Smith-Torhan
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Hongtao Zhang
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Blair C. Weig
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Ginny Ho
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Deen Tulshian
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Maurine E. Linder
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Michael P. Graziano
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Abstract

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.

Footnotes

    • Received June 14, 2000.
    • Accepted September 22, 2000.
  • Send reprint requests to: Ahmad B. Fawzi, Ph.D., Schering-Plough Research Institute, 2015 Galloping Hill Rd., K15-C405 (4600), Kenilworth, NJ 07033-0539. E-mail:ahmad.fawzi{at}spcorp.com

  • ↵1 Present address: CNS Biochemical Pharmacology, Aventis Pharmaceuticals, Bridgewater, New Jersey.

  • This work was supported by United States Public Health Services Grant GM51466 (M.E.L.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (1)
Molecular Pharmacology
Vol. 59, Issue 1
1 Jan 2001
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Research ArticleArticle

SCH-202676: An Allosteric Modulator of Both Agonist and Antagonist Binding to G Protein-Coupled Receptors

Ahmad B. Fawzi, Douglas Macdonald, Lawrence L. Benbow, April Smith-Torhan, Hongtao Zhang, Blair C. Weig, Ginny Ho, Deen Tulshian, Maurine E. Linder and Michael P. Graziano
Molecular Pharmacology January 1, 2001, 59 (1) 30-37; DOI: https://doi.org/10.1124/mol.59.1.30

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Research ArticleArticle

SCH-202676: An Allosteric Modulator of Both Agonist and Antagonist Binding to G Protein-Coupled Receptors

Ahmad B. Fawzi, Douglas Macdonald, Lawrence L. Benbow, April Smith-Torhan, Hongtao Zhang, Blair C. Weig, Ginny Ho, Deen Tulshian, Maurine E. Linder and Michael P. Graziano
Molecular Pharmacology January 1, 2001, 59 (1) 30-37; DOI: https://doi.org/10.1124/mol.59.1.30
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