Activation of the G-Protein-Coupled Receptor 119: A Conformation-Based Hypothesis for Understanding Agonist Response

• Published in: Journal of medicinal chemistry Vol. 54; no. 6; pp. 1948 - 1952
• Main Authors: McClure, Kim F, Darout, Etzer, Guimarães, Cristiano R. W, DeNinno, Michael P, Mascitti, Vincent, Munchhof, Michael J, Robinson, Ralph P, Kohrt, Jeffrey, Harris, Anthony R, Moore, Dianna E, Li, Bryan, Samp, Lacey, Lefker, Bruce A, Futatsugi, Kentaro, Kung, Daniel, Bonin, Paul D, Cornelius, Peter, Wang, Ruduan, Salter, Eben, Hornby, Sam, Kalgutkar, Amit S, Chen, Yue
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24-03-2011
• Subjects: Animals; Azabicyclo Compounds - chemical synthesis; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - pharmacology; Glucose Tolerance Test; Humans; Molecular Conformation; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Species Specificity; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200003p

The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.