The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery. 1. Introduction The glucagon-like peptide-1 (GLP-1) receptor is a member of the peptide hormone binding class B1 (secretin-like receptors) family of seven transmembrane spanning, heterotrimeric G-protein coupled receptors (GPCRs). The best characterized physiologic role of the GLP-1 receptor is to help regulate insulin secretion from pancreatic β cells [1]. GLP-1 binding to the receptor activates Gαs, stimulating membrane-associated adenylyl cyclases and cyclic 3′5′AMP (cAMP) production which enhances glucose dependent insulin secretion. The GLP-1 receptor peptide agonists, exenatide (exendin-4) and liraglutide, are widely approved medicines for the treatment of type 2 diabetes mellitus (T2DM) [2]. Identifying and developing small molecular weight organic compounds that mimic the orthosteric binding and receptor activation properties of GLP-1 peptide agonists is difficult. Class A GPCRs, for which many therapeutic small molecules have been developed [3], are structurally distinct from class B1 GPCRs. Class B1 receptors contain a larger independently folded globular ectodomain (ECD) at their N-termini. Peptide ligand binding to the ECD to initiate signaling of class B1 GPCRs is mechanistically different compared to class A receptors whose ligands primarily make contact with residues located within the membrane spanning α-helical regions [4]. For class B1 receptors, peptide ligands make numerous contacts with the ECD and extracellular loops of the transmembrane bundle [4]. For class A receptors, medicinal chemistry efforts have successfully exploited the endogenous ligand binding sites within transmembrane
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