ro-4956371 and Fragile-X-Syndrome

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.

Topics: Allosteric Regulation; Animals; Depression; Dose-Response Relationship, Drug; Drug Discovery; Fragile X Syndrome; Humans; Imidazoles; Macaca mulatta; Male; Mice; Mice, Inbred Strains; Molecular Structure; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Structure-Activity Relationship

Fragile X syndrome (FXS) is the most common genetic cause for intellectual disability. Fmr1 knockout (KO) mice are an established model of FXS. Chronic pharmacological inhibition of metabotropic glutamate receptor 5 (mGlu5) in these mice corrects multiple molecular, physiological, and behavioral phenotypes related to patients' symptoms. To better understand the pathophysiology of FXS and the effect of treatment, brain activity was analyzed using functional magnetic resonance imaging in relation to learning and memory performance.. Wild-type (WT) and Fmr1 KO animals receiving chronic treatment with the mGlu5 inhibitor CTEP or vehicle were evaluated consecutively for 1) learning and memory performance in the inhibitory avoidance and extinction test, and 2) for the levels of brain activity using continuous arterial spin labeling based functional magnetic resonance imaging. Neural activity patterns were correlated with cognitive performance using a multivariate regression analysis. Furthermore, mGlu5 receptor expression in brains of untreated mice was analyzed by autoradiography and saturation analysis using [(3)H]-ABP688.. Chronic CTEP treatment corrected the learning deficit observed in Fmr1 KO mice in the inhibitory avoidance and extinction test and prevented memory extinction in WT and Fmr1 KO animals. Chronic CTEP treatment normalized perfusion in the amygdala and the lateral hypothalamus in Fmr1 KO mice and furthermore decreased perfusion in the hippocampus and increased perfusion in primary sensorimotor cortical areas. No significant differences in mGlu5 receptor expression levels between Fmr1 WT and KO mice were detected.. Chronic mGlu5 inhibition corrected the learning deficits and partially normalized the altered brain activity pattern in Fmr1 KO mice.

Topics: Animals; Avoidance Learning; Brain; Cognition; Disease Models, Animal; Electroshock; Excitatory Amino Acid Antagonists; Extinction, Psychological; Fragile X Mental Retardation Protein; Fragile X Syndrome; Imidazoles; Mice; Mice, Knockout; Oximes; Oxygen; Pyridines; Receptor, Metabotropic Glutamate 5; Tritium

Treatment for fragile X syndrome and related autism spectrum disorders has long been thought to be effective only during a narrow window early in development. In this issue of Neuron, Michalon et al. (2012) dispel this myth.

Topics: Animals; Excitatory Amino Acid Antagonists; Fragile X Syndrome; Imidazoles; Male; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.

Topics: Age Factors; Animals; Disease Models, Animal; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Fragile X Mental Retardation Protein; Fragile X Syndrome; Hippocampus; Imidazoles; Male; Mice; Mice, Knockout; Phenotype; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate