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Glossary Abbreviations Used AE adverse event AUC area under the plasma concentration versus time curve βArr β-arrestin βArr1 β-arrestin-1 βArr2 β-arrestin-2 BETP 4-[3-(benzyloxy)phenyl]-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine cAMP cyclic adenosine monophosphate CHO Chinese hamster ovary CL int intrinsic clearance CL p high plasma clearance C max maximal plasma concentration cryo-EM cryogenic electron microscope CS candidate selection ECD extracellular domain EC 50 half-maximal effective concentration E max maximal effect FAP fluorogen-activated protein Gαs guanine nucleotide-binding α stimulatory subunit GFP green fluorescent protein GLP-1R glucagon-like peptide-1 receptor GPCR G protein-coupled receptor HbA1c glycated hemoglobin HEK human embryonic kidney hERG human ether-a-go-go-related gene HLM human liver microsomes HPLC high-performance liquid chromatography HTS high-throughput screening IR immediate release iv intravenous IVGTT intravenous glucose tolerance test K i inhibition constant NMR nuclear magnetic resonance PAM positive allosteric modulator PDB Protein Data Bank po oral RO receptor occupancy S serine SA screening assay SAR structure–activity relationship SEM standard error of the mean t 1/2 elimination half-life T2DM type 2 diabetes mellitus T max median time to reach C max W tryptophan Supporting Information Available The Supporting Information is available free of charge at Tables S1–S7 with supporting GLP-1R pharmacology data and off-target pharmacology data