ABSTRACT
Epilepsy is a common neurological disorder characterized by abnormal activity of neuronal networks, leading to seizures. The racetam class of anti-seizure medications bind specifically to a membrane protein found in the synaptic vesicles of neurons called synaptic vesicle protein 2 (SV2) A (SV2A). SV2A belongs to an orphan subfamily of the solute carrier 22 organic ion transporter family that also includes SV2B and SV2C. The molecular basis for how anti-seizure medications act on SV2s remains unknown. Here we report cryo-electron microscopy structures of SV2A and SV2B captured in a luminal-occluded conformation complexed with anticonvulsant ligands. The conformation bound by anticonvulsants resembles an inhibited transporter with closed luminal and intracellular gates. Anticonvulsants bind to a highly conserved central site in SV2s. These structures provide blueprints for future drug design and will facilitate future investigations into the biological function of SV2s.
ABSTRACT
A series of potent carboxylic acid DGAT1 inhibitors with high permeability were developed from a virtual screening hit. Strategies were employed to reduce Pgp substrate recognition and increase passive permeability, resulting in the discovery of a series showing good inhibition of cellular triglyceride synthesis. The mutagenic potential of prospective metabolites was evaluated in the Ames assay, and one aniline was shown to be devoid of mutagenicity.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Caco-2 Cells , Diacylglycerol O-Acyltransferase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Permeability/drug effects , Structure-Activity RelationshipABSTRACT
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
Subject(s)
Glucokinase/metabolism , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Animals , Enzyme Activation , Female , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/enzymology , Rats , Rats, Sprague-Dawley , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Sulfones/adverse effects , Sulfones/pharmacokinetics , Thiazoles/adverse effects , Thiazoles/pharmacokineticsABSTRACT
BACKGROUND: GPR119 is a Gαs-protein-coupled receptor expressed predominantly in pancreatic islets and gastrointestinal tract in humans. OBJECTIVE/METHODS: To review the available literature on GPR119 agonists. RESULTS: GPR119 de-orphanisation indicates two classes of possible endogenous agonists, phospholipids and fatty acid amides, with oleoylethanolamide and N-oleoyldopamine being the most potent. GPR119 agonists increase intracellular cAMP leading to increased glucose-dependent insulin secretion from pancreatic ß-cells and incretin secretion from gut enteroendocrine cells. In various animal models of type 2 diabetes and obesity, orally available, potent, selective, synthetic GPR119 agonists: i) lower blood glucose without hypoglycaemia; ii) slow diabetes progression; and iii) reduce food intake and body weight. CONCLUSIONS: Oral GPR119 agonists may have the potential to achieve blood glucose control together with body weight loss in type 2 diabetics, an outcome only achievable currently with injectable glucagon-like peptide 1 receptor agonists.
ABSTRACT
The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
Subject(s)
Appetite Depressants/pharmacology , Feeding Behavior/drug effects , Oleic Acids/metabolism , Oleic Acids/pharmacology , Receptors, G-Protein-Coupled/metabolism , Animals , Appetite Depressants/administration & dosage , Appetite Depressants/chemistry , Cyclic AMP/metabolism , Diet , Dose-Response Relationship, Drug , Endocannabinoids , Humans , Male , Mice , Molecular Sequence Data , Obesity/drug therapy , Oleic Acids/administration & dosage , Oleic Acids/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/genetics , Substrate Specificity , Time Factors , Yeasts/metabolismABSTRACT
The synthesis, SAR and biological evaluation of a series of ureas that activate glucokinase, a target for diabetes therapy as a result of its critical role in the regulation of whole-body glucose homeostasis, are described. Some of the urea-containing glucokinase activators lowered blood glucose levels in vivo following oral dosing to C57BL/6J mice.
