Benzimidazoles as potent and orally active mGlu5 receptor antagonists with an improved PK profile

A focused chemical optimization effort of compound 1 based on metabolite elucidation is described, resulting in 15i, a highly potent and selective mGlu5 receptor antagonist with an improved pharmacokinetic profile compared to 1. Characterization of 15i in vivo in the fear-potentiated startle (FPS) paradigm revealed a robust reduction of conditioned fear behavior. This effect nicely correlates with the rat brain pharmacokinetics

Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity

High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation

Discovery of 1H-pyrrolo[2,3-c]pyridine-7-carboxamides as novel, allosteric mGluR5 antagonists

1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed improving the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency

Regional brain mGlu5 receptor occupancy following single oral doses of mavoglurant as measured by [11C]-ABP688 PET imaging in healthy volunteers

Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as [11C]-ABP688, a radioligand. This open-label, single-center pilot study estimates extent of occupancy of mGluR5 receptors following single oral doses of mavoglurant, using [11C]-ABP688 positron emission tomography (PET) imaging, in six healthy males aged 20–40 years. This study comprised three periods and six subjects were divided into two cohorts. On Day 1 (Period 1), baseline clinical data and safety samples were obtained along with PET scan. During Period 2 (1–7 days after Period 1), cohort 1 and 2 received mavoglurant 25 mg and 100 mg, respectively. During Period 3 (7 days after Period 2), cohort 1 and 2 received mavoglurant 200 mg and 400 mg, respectively. Mavoglurant showed the highest distribution volumes in the cingulate region with lower uptake in cerebellum and white matter, possibly because myelinated axonal sheets maybe devoid of mGlu5 receptors. Maximum concentrations of mavoglurant were observed around 2–3.25 h post-dose. Mavoglurant passed the blood–brain barrier and induced dose- and exposure-dependent displacement of [11C]-ABP688 from the mGluR5 receptors, 3–4 h post-administration (27%, 59%, 74%, 85% receptor occupancy for mavoglurant 25 mg, 100 mg, 200 mg, 400 mg dose, respectively). There were no severe adverse effects or clinically significant changes in safety parameters. This is the first human receptor occupancy study completed with Mavoglurant. It served to guide the dosing of mavoglurant in the past and currently ongoing clinical studies. Furthermore, it confirms the utility of [11C]-ABP688 as a unique tool to study drug-induced occupancy of mGlu5 receptors in the living human brain

AFQ056/Mavoglurant a novel clinically effective mGluR5 antagonist: Identification, SAR and pharmacological characterization.

Here we describe the identification, structure-activity relationship and the initial pharmacological characterization of AFQ056/mavoglurant, a structurally novel, non-competitive mGlu5 receptor antagonist. AFQ056/mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/mavoglurant had an IC50 of 30 nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes. In vivo, AFQ056/mavoglurant showed an improved pharmacokinetic profile in rat and efficacy in the stress-induced hyperthermia test in mice as compared to the prototypic mGluR5 antagonist MPEP. The efficacy of AFQ056/mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson’s disease and Fragile X syndrome in proof of principle clinical studies

Quinazolinedione sulfonamides: A Novel Class of Competitive AMPA Receptor Antagonists with Oral Activity

Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models

ABP688, a novel selective and high affinity ligand for the labeling of mGlu5 receptors: identification, in vitro pharmacology, pharmacokinetic and biodistribution studies.

[(11)C]ABP688 (2) has recently been demonstrated to be a useful PET tracer for in vivo imaging of the metabotropic glutamate receptors type 5 (mGluR5) in rodents. We describe here the identification and preclinical profiling of ABP688 and its tritiated version [(3)H]ABP688, and show that its high affinity (K(d)=2nM), selectivity, and pharmacokinetic properties fulfill all requirements for development as a PET tracer for clinical imaging of the mGlu5 receptor

Differential roles of mGlu7 and mGlu8 in amygdala physiology and in amygdala-dependent behavior

Glutamate transmission within the amygdala is crucial for amygdaloid plasticity and the learning and expression of conditioned fear. Glutamate activates both ionotropic glutamate receptors and eight subtypes of metabotropic glutamate receptors (mGlu1-8). In the present study, the roles of mGlu7 and mGlu8 in different in vitro and in vivo paradigms of amygdaloid plasticity and behavior were investigated. We show that mGlu7-deficient but not mGlu8-deficient mice have attenuated long-term potention (LTP) within the amygdala. mGlu7-deficient mice express a general deficit in conditioned fear wheras in mGlu8-deficient mice, only contextual fear is strongly reduced . The mGlu7 agonist AMN082 reduces amygdaloid LTP and blocks the learning of conditioned fear after intra-amygdala injections. In contrast, the mGlu8 agonist DCPG decreased synaptic transmission within the amygdala but not LTP. Intra-amygdala injections of DCPG do only affect expression of contextual fear but not the learning and expression of cued fear. Taken together, these data revealed very different roles for amygdaloid mGlu7 and mGlu8 in the learning and expression of conditioned fear. Both receptors may be promising targets for the treatment of anxiety disorders; mGlu7 for anxiety disorders with pathological fear learning and mGlu8 for anxiety disorders with exaggerated contextual fear

Inhibition of Amygdala Plasticity, Stress and Anxiety Behavior by Blocking at the Venus Flytrap Domain (VFTD) of the Metabotropic Glutamate Receptor Subtype 7 (mGlu7)

The metabotropic glutamate receptor subtype 7 (mGlu7) acts as important presynaptic regulator of neurotransmission in the mammalian CNS and has been linked, via the use of behavioral genetics and pharmacology, to various psychiatric conditions including autism, drug abuse, anxiety and depression. Despite this, it has been difficult to develop specific blockers of native mGlu7 signaling in relevant brain areas such as amygdala and limbic cortex. Here, we present the mGlu7-selective antagonist XAP044 [7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one] which inhibits lateral amygdala long-term potentiation (LTP) in slices from wildtype mice with a half-maximal blockade at 88 nM. There was no effect of XAP044 on this LTP of mGlu7-deficient mice indicating that the effect was due to mGlu7 antagonism. Unexpectedly and in contrast to all previous mGlu7-selective ligands, XAP044 binds to a novel molecular pocket that localizes in mGlu7’s extracellular Venus flytrap domain (VFTD), which is generally known for orthosteric agonist binding. This was shown by chimeric receptor studies in recombinant cell line assays. In rodent behavioral analysis, XAP044 demonstrates wide-spectrum antistress, antidepressant-like, and anxiolytic efficacy, including less freezing during acquisition of Pavlovian fear and reduced innate anxiety, which is well consistent with the phenotypes of mGlu7-deficient mice, mGlu7 siRNA knockdown studies and with our amygdala LTP effects of XAP044. Taken together, we here provide a novel molecular mode of pharmacological action with significant application potential in psychiatry, i.e. blocking mGlu7 signaling via its VFTD, who’s high-resolution 3D-structure is known, which may facilitate future drug development via the use of computer-assisted drug design