Roger L. Robey

Bio: Roger L. Robey is an academic researcher from Eli Lilly and Company. The author has contributed to research in topics: Agonist & Enantiomer. The author has an hindex of 8, co-authored 16 publications receiving 637 citations.

Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties.

Abstract: 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (τ1 and τ2) which determine the relative positions of the α-amino acid and distal carboxyl functionalities are constrained where τ1 = 166.9° or 202° and τ 2 = 156°, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (±)-9, its C2-diastereomer (±)-16, and its enantiomers (+)-9 (LY354740) and (−)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (±)-9 (EC50 = 0.086 ± 0.025 μM) and its enantiomer (+)-9 (EC50 = 0.055 ± 0.017 μM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice pre...

Design, Synthesis, and Pharmacological Characterization of (+)-2- Aminobicyclo(3.1.0)hexane-2,6-dicarboxylic Acid (LY354740): A Potent, Selective, and Orally Active Group 2 Metabotropic Glutamate Receptor Agonist Possessing Anticonvulsant and Anxiolytic Properties.

Abstract: 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (τ1 and τ2) which determine the relative positions of the α-amino acid and distal carboxyl functionalities are constrained where τ1 = 166.9° or 202° and τ 2 = 156°, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (±)-9, its C2-diastereomer (±)-16, and its enantiomers (+)-9 (LY354740) and (−)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (±)-9 (EC50 = 0.086 ± 0.025 μM) and its enantiomer (+)-9 (EC50 = 0.055 ± 0.017 μM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice pre...

A Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist with a Unique in Vitro Profile and Potent Glucose and Lipid Effects in Rodent Models of Type 2 Diabetes and Dyslipidemia

Abstract: LSN862 is a novel peroxisome proliferator-activated receptor (PPAR)α/γ dual agonist with a unique in vitro profile that shows improvements on glucose and lipid levels in rodent models of type 2 diabetes and dyslipidemia. Data from in vitro binding, cotransfection, and cofactor recruitment assays characterize LSN862 as a high-affinity PPARγ partial agonist with relatively less but significant PPARα agonist activity. Using these same assays, rosiglitazone was characterized as a high-affinity PPARγ full agonist with no PPARα activity. When administered to Zucker diabetic fatty rats, LSN862 displayed significant glucose and triglyceride lowering and a significantly greater increase in adiponectin levels compared with rosiglitazone. Expression of genes involved in metabolic pathways in the liver and in two fat depots from compound-treated Zucker diabetic fatty rats was evaluated. Only LSN862 significantly elevated mRNA levels of pyruvate dehydrogenase kinase isozyme 4 and bifunctional enzyme in the liver and l...

Animal models in type 2 diabetes research: an overview.

Abstract: Type 2 diabetes is a complex and heterogeneous disorder presently affecting more than 100 million people worldwide and causing serious socio-economic problems. Appropriate experimental models are essential tools for understanding the pathogenesis, complications, and genetic or environmental influences that increase the risks of type 2 diabetes and testing of various therapeutic agents. The animal models of type 2 diabetes can be obtained either spontaneously or induced by chemicals or dietary or surgical manipulations and/or by combination thereof. In recent years, large number of new genetically modified animal models including transgenic, generalized knock-out and tissue-specific knockout mice have been engineered for the study of diabetes. This review gives an overview on the animal models of type 2 diabetes with reference to their origin/source, characteristic features, underlying causes/mechanism(s), advantages and disadvantages to the investigators in diabetes research. In addition, it especially describes the appropriate selection and usefulness of different animal models in preclinical testing of various new chemical entities (NCEs) for the treatment of type 2 diabetes.

Ionotropic and metabotropic glutamate receptor structure and pharmacology

Abstract: l-Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) and mediates its actions via activation of both ionotropic and metabotropic receptor families. The development of selective ligands, including competitive agonists and antagonists and positive and negative allosteric modulators, has enabled investigation of the functional roles of glutamate receptor family members. In this review we describe the subunit structure and composition of the ionotropic and metabotropic glutamate receptors and discuss their pharmacology, particularly with respect to selective tools useful for investigation of their function in the CNS. A large number of ligands are now available that are selective either for glutamate receptor subfamilies or for particular receptor subtypes. Such ligands have enabled considerable advances in the elucidation of the physiological and pathophysiological roles of receptor family members. Furthermore, efficacy in animal models of neurological and psychiatric disorders has supported the progression of several glutamatergic ligands into clinical studies. These include ionotropic glutamate receptor antagonists, which have entered clinical trials for disorders including epilepsy and ischaemic stroke, α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor positive allosteric modulators which are under evaluation as cognitive enhancers, and metabotropic glutamate receptor 2 (mGluR2) agonists which are undergoing clinical evaluation as anxiolytics. Furthermore, preclinical studies have illustrated therapeutic potential for ligands selective for other receptor subtypes in various disorders. These include mGluR1 antagonists in pain, mGluR5 antagonists in anxiety, pain and drug abuse and mGluR5 positive allosteric modulators in schizophrenia. Selective pharmacological tools have enabled the study of glutamate receptors. However, pharmacological coverage of the family is incomplete and considerable scope remains for the development of novel ligands, particularly those with in vivo utility, and for the their use together with existing tools for the further investigation of the roles of receptor family members in CNS function and as potentially novel therapeutics.

Metabotropic glutamate receptors as novel targets for anxiety and stress disorders

Abstract: Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu(1) and mGlu(5)), group II (mGlu(2) and mGlu(3)), and group III (mGlu(4), mGlu(7) and mGlu(8)) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu(2/3)) receptors and antagonists for group I (in particular mGlu(5)) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.

Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus.

Abstract: The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDA-evoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity.