TY - JOUR T1 - Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes JF - Pharmacological Reviews JO - Pharmacol Rev SP - 954 LP - 1013 DO - 10.1124/pr.115.011395 VL - 68 IS - 4 AU - Chris de Graaf AU - Dan Donnelly AU - Denise Wootten AU - Jesper Lau AU - Patrick M. Sexton AU - Laurence J. Miller AU - Jung-Mo Ahn AU - Jiayu Liao AU - Madeleine M. Fletcher AU - Dehua Yang AU - Alastair J. H. Brown AU - Caihong Zhou AU - Jiejie Deng AU - Ming-Wei Wang A2 - DEQUAN YE, RICHARD Y1 - 2016/10/01 UR - http://pharmrev.aspetjournals.org/content/68/4/954.abstract N2 - The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein–coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a two-domain–binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidic GLP-1R agonists have been hampered, small-molecule modulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders. ER -