ABSTRACT
Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Incretins/metabolism , Insulin Secretion , Receptors, G-Protein-Coupled/agonists , Allosteric Site/genetics , Animals , Benzofurans/pharmacology , Benzofurans/therapeutic use , Crystallography, X-Ray , Diabetes Mellitus, Type 2/metabolism , Drug Synergism , HEK293 Cells , Humans , Hypoglycemic Agents/therapeutic use , Insulin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Molecular Docking Simulation , Mutagenesis, Site-Directed , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sulfones/pharmacology , Sulfones/therapeutic use , gamma-Linolenic Acid/metabolismABSTRACT
PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
Subject(s)
Cinnamates/chemical synthesis , Cinnamates/pharmacokinetics , Peroxisome Proliferator-Activated Receptors/physiology , Humans , Hypoglycemic Agents/therapeutic use , Ligands , PPAR alpha/physiology , PPAR gamma/physiology , Structure-Activity Relationship , Thiazolidinediones/chemical synthesis , Thiazolidinediones/therapeutic useABSTRACT
The tremendous increase in the global prevalence of Type 2 diabetes (T2D) and its conglomeration of metabolic disorders has dramatically intensified the search for innovative therapies to fight this emerging epidemic. Over the last decade, the family of nuclear receptors, especially the peroxisome proliferator-activated receptors (PPARs), has emerged as one of the most important drug targets aimed at combating the metabolic syndrome. Consequently, compounds that activate the PPARs have served as potential therapeutics for the treatment of T2D and the metabolic anomalies associated with this disorder. This review focuses on the currently marketed compounds and also describes the discovery and development of the next generation of PPAR ligands that are under investigation for the potential treatment of T2D and the metabolic syndrome.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Drugs, Investigational/therapeutic use , Hypoglycemic Agents/therapeutic use , PPAR gamma/agonists , Adipocytes/metabolism , Animals , Cardiovascular Diseases/chemically induced , Clinical Trials as Topic , Cricetinae , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/metabolism , Drug Design , Drug Evaluation, Preclinical , Drugs, Investigational/pharmacology , Drugs, Investigational/toxicity , Dyslipidemias/drug therapy , Gene Expression Regulation/drug effects , Glucose/metabolism , Humans , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/pharmacology , Hypolipidemic Agents/therapeutic use , Insulin/metabolism , Insulin Resistance , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Lipid Metabolism/drug effects , Metabolic Syndrome/complications , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Mice , Mice, Mutant Strains , Muscle Cells/metabolism , Organ Specificity , PPAR alpha/agonists , PPAR delta/agonists , PPAR delta/physiology , PPAR gamma/chemistry , PPAR gamma/physiology , Protein Isoforms/drug effects , Protein Isoforms/physiology , Rats , Rats, Sprague-Dawley , Rats, Zucker , Weight Gain/drug effectsABSTRACT
As the incidence of Type 2 diabetes has reached near epidemic proportions, the quest for novel therapies to combat this disorder has intensified dramatically. In recent years, the peroxisome proliferator-activated receptor (PPAR) family has received tremendous attention as perhaps an ideal target class to address the multiple metabolic anomalies associated with the diabetic state. This review focuses on a variety of novel PPAR approaches currently being investigated for Type 2 diabetes or the metabolic syndrome, including the highly potent selective PPAR agonists, PPAR combination agonists and alternative PPAR ligands.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Metabolic Syndrome/drug therapy , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Transcription Factors/agonists , Transcription Factors/antagonists & inhibitors , Diabetes Mellitus, Type 2/metabolism , Humans , Ligands , Metabolic Syndrome/metabolism , Transcription Factors/pharmacologyABSTRACT
The oxysterol receptors LXR (liver X receptor)-alpha and LXRbeta are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.