title: A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification.
abstract: We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro-3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Whitney M
authors.initials: WM
authors.lastname: Nolte
authors.affiliation: Cardiovascular and Metabolic Diseases Research Unit, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Fortin
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Stevens
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Aspnes
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.affiliation: Structural Biology and Biophysics Group, Center for Chemistry Innovation and Excellence, Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.
authors.forename: Lise R
authors.initials: LR
authors.lastname: Hoth
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Ruggeri
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D003545:Cysteine / Q000737:chemistry; D052216:Glucagon-Like Peptide 1 / Q000819:agonists; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008024:Ligands; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism; D018027:Receptors, Glucagon / Q000737:chemistry / Q000378:metabolism*
chemical_list: C570819:4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D011743:Pyrimidines; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D003545:Cysteine