Is there a path forward for mGlu(2) positive allosteric modulators for the treatment of schizophrenia?
Ontology highlight
ABSTRACT:
SUBMITTER: Hopkins CR
PROVIDER: S-EPMC3582287 | biostudies-other | 2013 Feb
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Using a functional high-throughput screening (HTS) and subsequent solution-phase parallel synthesis approach, we have discovered a novel series of positive allosteric modulators for mGlu?, a G-protein coupled receptor. This series is comprised of a homopiperazine central core. The solution-phase parallel synthesis and SAR of analogs derived from this series will be presented. This series of positive allosteric modulators of mGlu? provide critical research tools to further probe the mGlu?-mediated effects in Parkinson's disease.
| S-EPMC3057427 | biostudies-literature
Project description:Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.
| S-EPMC4096224 | biostudies-literature
Project description:Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.
| S-EPMC4748441 | biostudies-literature
Project description:?-Opioid receptors are among the most studied G protein-coupled receptors because of the therapeutic value of agonists, such as morphine, that are used to treat chronic pain. However, these drugs have significant side effects, such as respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Efforts to fine tune pain control while alleviating the side effects of drugs, both physiological and psychological, have led to the development of a wide variety of structurally diverse agonist ligands for the ?-opioid receptor, as well as compounds that target ?- and ?-opioid receptors. In recent years, the identification of allosteric ligands for some G protein-coupled receptors has provided breakthroughs in obtaining receptor subtype-selectivity that can reduce the overall side effect profiles of a potential drug. However, positive allosteric modulators (PAMs) can also have the specific advantage of only modulating the activity of the receptor when the orthosteric agonist occupies the receptor, thus maintaining spatial and temporal control of receptor signaling in vivo. This second advantage of allosteric modulators may yield breakthroughs in opioid receptor research and could lead to drugs with improved side-effect profiles or fewer tolerance and dependence issues compared with orthosteric opioid receptor agonists. Here, we describe the discovery and characterization of ?-opioid receptor PAMs and silent allosteric modulators, identified from high-throughput screening using a ?-arrestin-recruitment assay.
| S-EPMC3696790 | biostudies-literature
Project description:Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.
| S-EPMC6952546 | biostudies-literature
Project description:Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu(5)) have remained attractive to researchers as potential therapies for a number of central nervous system related diseases, including anxiety, pain, gastroesophageal reflux disease (GERD), addiction, Parkinson's disease (PD), and fragile X syndrome (FXS). In addition to the many publications with supportive preclinical data with key tool molecules, recent positive reports from the clinic have bolstered the confidence in this approach. During the two year time span from 2009 through 2010, a number of new mGlu(5) NAM chemotypes have been disclosed and discussed in the primary and patent literature. A summary of several efforts representing many diverse chemotypes are presented here, along with a discussion of representative structure activity relationships (SAR) and synthetic approaches to the templates where possible.
| S-EPMC3172159 | biostudies-other
Project description:Antagonist effects at the P2X(7) receptor are complex with many behaving in a non-competitive manner. In this study, the effects of N-[2-({2-[(2-hydroxyethyl)amino]ethyl}amino)-5-quinolinyl]-2-tricyclo[3.3.1.1(3,7)]dec-1-ylacetamide (compound-17) and N (2)-(3,4-difluorophenyl)-N (1)-[2-methyl-5-(1-piperazinylmethyl)phenyl]glycinamide dihydrochloride (GW791343) on P2X(7) receptors were examined and their mechanism of action explored.Antagonist effects were studied by measuring agonist-stimulated ethidium accumulation in cells expressing human or rat recombinant P2X(7) receptors and in radioligand binding studies.Compound-17 and GW791343 were non-competitive inhibitors of human P2X(7) receptors. Receptor protection studies using decavanadate and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) showed that neither compound-17 nor GW791343 competitively interacted at the ATP binding site and so were probably negative allosteric modulators of the P2X(7) receptor. GW791343 prevented the slowly reversible blockade of the human P2X(7) receptor produced by compound-17 and inhibited [(3)H]-compound-17 binding to the P2X(7) receptor suggesting they may bind to similar or interacting sites. At rat P2X(7) receptors, compound-17 was a negative allosteric modulator but the predominant effect of GW791343 was to increase agonist responses. Antagonist interaction and radioligand binding studies revealed that GW791343 did not interact at the ATP binding site but did interact with the compound-17 binding site suggesting that GW791343 is a positive allosteric modulator of the rat P2X(7) receptor.Compound-17 was a negative allosteric modulator of human and rat P2X(7) receptors. GW791343 was a negative allosteric modulator of the human P2X(7) receptor but at the rat P2X(7) receptor its predominant effect was positive allosteric modulation. These compounds should provide valuable tools for mechanistic studies on P2X(7) receptors.
| S-EPMC2259211 | biostudies-other
Project description:Alzheimer's disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer's diseases and other diseases characterized by cognitive impairment.
| S-EPMC8391421 | biostudies-literature
Project description:Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the "hinge" in the ligand-binding core "clamshell" that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.
| S-EPMC6725607 | biostudies-literature
Project description:Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu(4) belongs to a subfamily of mGlus that is predominantly coupled to G(i/o) G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu(4)-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu(4) depends upon the presence of H(1) histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu(4)-mediated signaling events downstream of G(i/o) G proteins, such as cAMP inhibition, suggesting that the presence of G(q) coupled receptors such as H(1) may bias normal mGlu(4)-mediated G(i/o) signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu(4) is assessed, the potentiated signaling of mGlu(4) is further biased by histamine toward calcium-dependent pathways. These results suggest that G(i/o)-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of G(q) receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when G(q) receptors are co-activated. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
| S-EPMC3412075 | biostudies-literature