mGlu5 Negative Allosteric Modulators Research Articles

Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators

A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs).

Substituted 1-Phenyl-3-(pyridin-2-yl)urea Negative Allosteric Modulators of mGlu5: Discovery of a New Tool Compound VU0463841 with Activity in Rat Models of Cocaine Addiction

Cocaine is a powerful and highly addictive stimulant that disrupts the normal reward circuitry in the central nervous system (CNS), producing euphoric effects. Cocaine use can lead to acute and life threatening emergencies, and abuse is associated with increased risk for contracting infectious diseases. Though certain types of behavioral therapy have proven effective for treatment of cocaine addiction, relapse remains high, and there are currently no approved medications for the treatment of cocaine abuse. Evidence has continued to accumulate that indicates a critical role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the modulation of neural circuitry associated with the addictive properties of cocaine. While the small molecule mGlu5 negative allosteric modulator (NAM) field is relatively advanced, investigation into the potential of small molecule mGlu5 NAMs for the treatment of cocaine addiction remains an area of high interest. Herein we describe the discovery and characterization of a potent and selective compound 29 (VU0463841) with good CNS exposure in rats. The utility of 29 (VU0463841) was demonstrated by its ability to attenuate drug seeking behaviors in relevant rat models of cocaine addiction.

ACS Chemical Neuroscience and Neuroscience Drug Discovery as 2012 Comes to a Close

Well, 2012 is almost over—hard to believe. ACS Chemical Neuroscience has now been publishing high quality neuroscience research for three years! The year 2012 presented several major milestones for ACS Chemical Neuroscience: we received our first impact factor (3.676) based on 2011 metrics, and we expanded our Associate Editors to include Dr. Anne Andrews (UCLA). In addition, both the number of manuscripts submitted to ACS Chemical Neuroscience and the number of citations to ACS Chemical Neuroscience manuscripts (Web of Science) has dramatically increased in 2012. In 2012, we also had our first thematic crossover issue with the Journal of Medicinal Chemistry and ACS Medicinal Chemistry Letters on Alzheimer’s disease (AD).1 From myself, the Associate Editors, and all at ACS, we want to extend a heartfelt thank you to all of the contributing authors to ACS Chemical Neuroscience since our launch in 2010, and for making ACS Chemical Neuroscience a desirable venue to publish your best neuroscience research. As for neuroscience drug discovery, 2012 witnessed a number of low points, with multiple companies pulling out of neuroscience drug discovery and a long list of phase II failures of CNS therapeutics (both small molecules and biologics), and in particular for AD1 and schizophrenia. Of these, the disappointing news that the Lilly mGlu2/3 agonist, Pomaglutamed Methionil, was unlikely to be positive in its primary end points in a phase III schizophrenia trial, that led the company to halt development.2 This is especially sad news, as the positive phase II data energized the industry with success of a nondopaminergic, novel mechanism for schizophrenic patients. However, as 2012 draws to a close, two bright lights have appeared. Janssen Pharmaceuticals and Addex Therapeutics announced that {type:entrez-protein,attrs:{text:ADX71149,term_id:323467462,term_text:ADX71149}}ADX71149, an mGlu2 positive allosteric modulator (PAM), demonstrated safety and tolerability as well as top-line data from a phase IIa monotherapy study in schizophrenic patients.3 A phase IIb trial is underway to explore the potential of the mGlu2 PAM as an adjunctive therapy with standard antipsychotics. Will the PAM succeed where the agonist failed? Speculation on neuroscience blogs suggests the agonist, with chronic dosing, may have desensitized the receptor. It will be most interesting to follow {type:entrez-protein,attrs:{text:ADX71149,term_id:323467462,term_text:ADX71149}}ADX71149 as it progresses through development to test the PAM mechanism, the target (mGlu2) and to offer a new therapeutic alternative to schizophrenic patients. Addex Therapeutics’ Dipraglurant, an mGlu5 negative allosteric modulator (NAM), was just named one of the “Top 10 Neuroscience Projects” to watch by Windhover and Virginia Herndon. Dipraglurant is an oral mGlu5 NAM that has demonstrated both safety and tolerability as well as efficacy in Parkinsons patients with leva-DOPA-induced diskinesias (LID).3 Efficacy was observed at both 50 and 100 mg doses. Moreover, Dipraglurant reduced dystonia severity and chorea, the two major components of LID. Overall, this is very exciting data for the approach of allosteric modulation of GPCRs and for patients suffering from LID; phase III data is eagerly awaited. In 2013, we plan to continue Viewpoint features on CNS therapeutics and solicit ideas and Viewpoints from the community. Again, we want ACS Chemical Neuroscience to also serve as a forum for scientific exchange on neuroscience and encourage your participation. We have a number of exciting things planned for 2013—visit the ACS Chemical Neuroscience Web site often for updates.

Targeting Glutamate Receptors to Tackle the Pathogenesis, Clinical Symptoms and Levodopa-Induced Dyskinesia Associated with Parkinson’s Disease

The appearance of levodopa-induced dyskinesia (LID) and ongoing degeneration of nigrostriatal dopaminergic neurons are two key features of Parkinson's disease (PD) that current treatments fail to address. Increased glutamate transmission contributes to the motor symptoms in PD, to the striatal plasticity that underpins LID and to the progression of neurodegeneration through excitotoxic mechanisms. Glutamate receptors have therefore long been considered as potential targets for pharmacological intervention in PD, with emphasis on either blocking activation of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA), N-methyl-D-aspartate (NMDA) or excitatory metabotropic glutamate (mGlu) 5 receptors or promoting the activation of group II/III mGlu receptors. Following a brief summary of the role of glutamate in PD and LID, this article explores the current status of pharmacological studies in pre-clinical rodent and primate models through to clinical trials, where applicable, that support the potential of glutamate-based therapeutic interventions. To date, AMPA antagonists have shown good efficacy against LID in rat and primate models, but the failure of perampanel to lessen LID in clinical trials casts doubt on the translational potential of this approach. In contrast, antagonists selective for NR2B-containing NMDA receptors were effective against LID in animal models and in small-scale clinical trials, though observed adverse cognitive effects need addressing. So far, mGlu5 antagonists or negative allosteric modulators (NAMs) look set to become the first introduced for tackling LID, with AFQ-056 reported to exhibit good efficacy in phase II clinical trials. NR2B antagonists and mGlu5 NAMs may subsequently prove to also be effective disease-modifying agents if their protective effects in rat and primate models of PD, respectively, are replicated in the next stages of investigation. Finally, group III mGlu4 agonists or positive allosteric modulators (PAMs), although in the early pre-clinical stages of investigation, are showing good efficacy against motor symptoms, neurodegeneration and LID. It is anticipated that the recent development of mGlu4 PAMs with improved systemic bioavailability will facilitate progression of these agents into the primate model of PD where their potential can be further explored.

Discovery of 2‐(2‐Benzoxazoyl amino)‐4‐Aryl‐5‐Cyanopyrimidine as Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptor 5 (mGlu5): From an Artificial Neural Network Virtual Screen to an In Vivo Tool Compound

Glutamate, the major excitatory neurotransmitter, functions in the brain via activation of ligand gated cation channels and also the eight subtypes of Class C G protein-coupled metabotropic glutamate receptors (mGlus).[1] Selective allosteric modulation of mGlu5 has been shown to have potential for treatment of a variety of neurological disorders[2,3] including anxiety disorders[4,5], Parkinson’s disease[6–8], Fragile X syndrome[9] and schizophrenia.[10–14] The majority of mGlu5 negative allosteric modulators (NAMs) developed to date either contain an alkyne moiety 1–4 or employ the alkyne topology as basis for ligand design,[15] as in 5–8 (Figure 1). Only recently have mGlu5 NAM chemotypes been identified, through high-throughput screening (HTS) campaigns, that are structurally unrelated to the classical acetylenic derivatives, such as 9–12 (Figure 1).[16] Due to the prevalence of ‘molecular switch‘phenomenon in MPEP related scaffolds, our interest focused on the discovery and development of novel mGlu5 NAM chemotypes, by both HTS and Artificial Neural Network (ANN) virtual screens.

Differential modulation of thresholds for intracranial self-stimulation by mGlu5 positive and negative allosteric modulators: implications for effects on drug self-administration

Pharmacological manipulation of the type 5 metabotropic glutamate (mGlu5) receptor alters various addiction related behaviors such as drug self-administration and the extinction and reinstatement of drug-seeking behavior. However, the effects of pharmacological modulation of mGlu5 receptors on brain reward function have not been widely investigated. We examined the effects of acute administration of positive and negative allosteric modulators (PAMs and NAMs, respectively) on brain reward function by assessing thresholds for intracranial self-stimulation (ICSS). In addition, when acute effects were observed, we examined changes in ICSS thresholds following repeated administration. Male Sprague-Dawley rats were implanted with bipolar electrodes into the medial forebrain bundle and trained to respond for ICSS, followed by assessment of effects of mGlu5 ligands on ICSS thresholds using a discrete trials current–intensity threshold determination procedure. Acute administration of the selective mGlu5 NAMs MTEP (0, 0.3, 1, or 3 mg/kg) and fenobam (0, 3, 10, or 30 mg/kg) dose-dependently increased ICSS thresholds (∼70% at the highest dose tested), suggesting a deficit in brain reward function. Acute administration of the mGlu5 PAMs CDPPB (0, 10, 30, and 60 mg/kg) or ADX47273 (0, 10, 30, and 60 mg/kg) was without effect at any dose tested. When administered once daily for five consecutive days, the development of tolerance to the ability of threshold-elevating doses of MTEP and fenobam to increase ICSS thresholds was observed. We conclude that mGlu5 PAMs and NAMs differentially affect brain reward function, and that tolerance to the ability of mGlu5 NAMs to reduce brain reward function develops with repeated administration. These brain reward deficits should be taken into consideration when interpreting acute effects of mGlu5 NAMs on drug self-administration, and repeated administration of these ligands may be an effective method to reduce these deficits.

CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor

The metabotropic glutamate receptor 5 (mGlu5) is a glutamate-activated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinson's disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [(3)H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED(50) equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30- to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.

Interactive effects of mGlu5 and 5-HT2A receptors on locomotor activity in mice

RationaleMetabotropic glutamate (mGlu) receptors have been suggested to play a role in neuropsychiatric disorders including schizophrenia, drug abuse, and depression. Because serotonergic hallucinogens increase glutamate release and mGlu receptors modulate the response to serotonin (5-HT)2A activation, the interactions between serotonin 5-HT2A receptors and mGlu receptors may prove to be important for our understanding of these diseases.ObjectiveWe tested the effects of the serotonergic hallucinogen and 5-HT2A agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), and the selective 5-HT2A antagonist, M100907, on locomotor activity in the mouse behavioral pattern monitor (BPM) in mGlu5 wild-type (WT) and knockout (KO) mice on a C57 background.ResultsBoth male and female mGlu5 KO mice showed locomotor hyperactivity and diminished locomotor habituation compared with their WT counterparts. Similarly, the mGlu5-negative allosteric modulator 2-methyl-6-(phenylethynyl)pyridine (MPEP) also increased locomotor hyperactivity, which was absent in mGlu5 KO mice. The locomotor hyperactivity in mGlu5 receptor KO mice was potentiated by DOM (0.5 mg/kg, subcutaneously (SC)) and attenuated by M100907 (1.0 mg/kg, SC). M100907 (0.1 mg/kg, SC) also blocked the hyperactivity induced by MPEP.ConclusionsThese studies demonstrated that loss of mGlu5 receptor activity either pharmacologically or through gene deletion leads to locomotor hyperactivity in mice. Additionally, the gene deletion of mGlu5 receptors increased the behavioral response to the 5-HT2A agonist DOM, suggesting that mGlu5 receptors either mitigate the behavioral effects of 5-HT2A hallucinogens or that mGlu5 KO mice show an increased sensitivity to 5-HT2A agonists. Taken together, these studies indicate a functional interaction between mGlu5 and 5-HT2A receptors.

Novel heterocyclic compounds as mGlu5 antagonists: WO2009015897

Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) have previously been implicated in a number of pathophysiological conditions, based on preclinical, and to some extent clinical, proof of concept for migraine, gastroesophageal reflux disease, Parkinson's disease and anxiety. In the past, the potential use of known mGlu5 antagonists for the treatment of lower urinary tract disorders was disclosed. In the patent evaluated herein, novel derivatives of 4-(prop-2-ynylidene)piperidine are described and claimed by Recordati Ireland Ltd, Ireland, as NAMs at mGlu5 for the treatment of lower urinary tract disorders. Selected compounds reported in this application were efficacious in the cystometry model of bladder dysfunction in conscious rats, and mGlu5 NAMs are, therefore, suggested to have potential for the treatment of lower urinary tract disorders.