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Mutual activation of glutamatergic mGlu and muscarinic M receptors reverses schizophrenia-related changes in rodents.
Cieślik P, Woźniak M, Rook JM, Tantawy MN, Conn PJ, Acher F, Tokarski K, Kusek M, Pilc A, Wierońska JM
(2018) Psychopharmacology (Berl) 235: 2897-2913
MeSH Terms: Amphetamine, Animals, Antipsychotic Agents, Disease Models, Animal, Dizocilpine Maleate, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists, Male, Mice, Motor Activity, Phosphinic Acids, Receptor, Muscarinic M4, Receptors, Metabotropic Glutamate, Rodentia, Schizophrenia
Show Abstract · Added April 11, 2019
RATIONALE - Metabotropic glutamate receptors and muscarinic M receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to G proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity.
OBJECTIVES - In the present studies, subactive doses of mGlu and M activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu and M receptors in animal models of schizophrenia.
METHODS - The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects.
RESULTS - The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D receptor levels in the striatum, as measured with [F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test.
CONCLUSIONS - Based on our results, the simultaneous activation of M and mGlu receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.
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MeSH Terms
Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies.
Joffe ME, Centanni SW, Jaramillo AA, Winder DG, Conn PJ
(2018) ACS Chem Neurosci 9: 2188-2204
MeSH Terms: Alcoholism, Animals, Humans, Limbic System, Neuronal Plasticity, Receptors, Metabotropic Glutamate, Synaptic Transmission
Show Abstract · Added March 26, 2019
Developing efficacious treatments for alcohol use disorder (AUD) has proven difficult. The insidious nature of the disease necessitates a deep understanding of its underlying biology as well as innovative approaches to ameliorate ethanol-related pathophysiology. Excessive ethanol seeking and relapse are generated by long-term changes to membrane properties, synaptic physiology, and plasticity throughout the limbic system and associated brain structures. Each of these factors can be modulated by metabotropic glutamate (mGlu) receptors, a diverse set of G protein-coupled receptors highly expressed throughout the central nervous system. Here, we discuss how different components of the mGlu receptor family modulate neurotransmission in the limbic system and other brain regions involved in AUD etiology. We then describe how these processes are dysregulated following ethanol exposure and speculate about how mGlu receptor modulation might restore such pathophysiological changes. To that end, we detail the current understanding of the behavioral pharmacology of mGlu receptor-directed drug-like molecules in animal models of AUD. Together, this review highlights the prominent position of the mGlu receptor system in the pathophysiology of AUD and provides encouragement that several classes of mGlu receptor modulators may be translated as viable treatment options.
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7 MeSH Terms
Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation.
Walker AG, Sheffler DJ, Lewis AS, Dickerson JW, Foster DJ, Senter RK, Moehle MS, Lv X, Stansley BJ, Xiang Z, Rook JM, Emmitte KA, Lindsley CW, Conn PJ
(2017) Neuropsychopharmacology 42: 2553-2566
MeSH Terms: Animals, Cerebral Cortex, Conditioning, Psychological, Cyclic AMP, Hippocampus, Long-Term Potentiation, Male, Memory Consolidation, Mice, Inbred ICR, Mice, Knockout, Neurotransmitter Agents, Rats, Sprague-Dawley, Receptors, Adrenergic, beta, Receptors, Metabotropic Glutamate, Tissue Culture Techniques
Show Abstract · Added March 21, 2018
Activation of β-adrenergic receptors (βARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal-dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with βARs in the hippocampal astrocytes induces a large increase in cyclic-AMP (cAMP) accumulation and release of adenosine. Adenosine then acts on A adenosine receptors at neighboring excitatory Schaffer collateral terminals, which could counteract effects of activation of neuronal βARs on excitatory transmission. On the basis of this, we postulated that activation of the specific mGlu receptor subtype that mediates this response could inhibit βAR-mediated effects on hippocampal synaptic plasticity and cognitive function. Using novel mGlu receptor subtype-selective allosteric modulators along with knockout mice we now report that the effects of mGlu agonists on βAR-mediated increases in cAMP accumulation are exclusively mediated by mGlu. Furthermore, mGlu activation inhibits the ability of the βAR agonist isoproterenol to enhance hippocampal LTP, and this effect is absent in slices treated with either a glial toxin or an adenosine A receptor antagonist. Finally, systemic administration of the mGlu agonist LY379268 disrupted contextual fear memory in a manner similar to the effect of the βAR antagonist propranolol, and this effect was reversed by the mGlu-negative allosteric modulator VU0650786. Taken together, these data suggest that mGlu can influence astrocytic signaling and modulate βAR-mediated effects on hippocampal synaptic plasticity and cognitive function.
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15 MeSH Terms
mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks.
Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AFT, Paspalas CD
(2018) Cereb Cortex 28: 974-987
MeSH Terms: Action Potentials, Animals, Dose-Response Relationship, Drug, Excitatory Amino Acid Agents, Eye Movements, Female, Image Processing, Computer-Assisted, Macaca mulatta, Magnetic Resonance Imaging, Male, Memory, Short-Term, Neurons, Post-Synaptic Density, Prefrontal Cortex, Rats, Receptors, Metabotropic Glutamate, Spatial Learning, Subcellular Fractions
Show Abstract · Added April 6, 2017
The newly evolved circuits in layer III of primate dorsolateral prefrontal cortex (dlPFC) generate the neural representations that subserve working memory. These circuits are weakened by increased cAMP-K+ channel signaling, and are a focus of pathology in schizophrenia, aging, and Alzheimer's disease. Cognitive deficits in these disorders are increasingly associated with insults to mGluR3 metabotropic glutamate receptors, while reductions in mGluR2 appear protective. This has been perplexing, as mGluR3 has been considered glial receptors, and mGluR2 and mGluR3 have been thought to have similar functions, reducing glutamate transmission. We have discovered that, in addition to their astrocytic expression, mGluR3 is concentrated postsynaptically in spine synapses of layer III dlPFC, positioned to strengthen connectivity by inhibiting postsynaptic cAMP-K+ channel actions. In contrast, mGluR2 is principally presynaptic as expected, with only a minor postsynaptic component. Functionally, increase in the endogenous mGluR3 agonist, N-acetylaspartylglutamate, markedly enhanced dlPFC Delay cell firing during a working memory task via inhibition of cAMP signaling, while the mGluR2 positive allosteric modulator, BINA, produced an inverted-U dose-response on dlPFC Delay cell firing and working memory performance. These data illuminate why insults to mGluR3 would erode cognitive abilities, and support mGluR3 as a novel therapeutic target for higher cognitive disorders.
© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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18 MeSH Terms
The Role of mGlu Receptors in Hippocampal Plasticity Deficits in Neurological and Psychiatric Disorders: Implications for Allosteric Modulators as Novel Therapeutic Strategies.
Senter RK, Ghoshal A, Walker AG, Xiang Z, Niswender CM, Conn PJ
(2016) Curr Neuropharmacol 14: 455-73
MeSH Terms: Allosteric Regulation, Animals, Excitatory Amino Acid Agents, Hippocampus, Humans, Mental Disorders, Neuronal Plasticity, Psychotropic Drugs, Receptors, Metabotropic Glutamate
Show Abstract · Added April 6, 2017
Long-term potentiation (LTP) and long-term depression (LTD) are two distinct forms of synaptic plasticity that have been extensively characterized at the Schaffer collateral-CA1 (SCCA1) synapse and the mossy fiber (MF)-CA3 synapse within the hippocampus, and are postulated to be the molecular underpinning for several cognitive functions. Deficits in LTP and LTD have been implicated in the pathophysiology of several neurological and psychiatric disorders. Therefore, there has been a large effort focused on developing an understanding of the mechanisms underlying these forms of plasticity and novel therapeutic strategies that improve or rescue these plasticity deficits. Among many other targets, the metabotropic glutamate (mGlu) receptors show promise as novel therapeutic candidates for the treatment of these disorders. Among the eight distinct mGlu receptor subtypes (mGlu1-8), the mGlu1,2,3,5,7 subtypes are expressed throughout the hippocampus and have been shown to play important roles in the regulation of synaptic plasticity in this brain area. However, development of therapeutic agents that target these mGlu receptors has been hampered by a lack of subtype-selective compounds. Recently, discovery of allosteric modulators of mGlu receptors has provided novel ligands that are highly selective for individual mGlu receptor subtypes. The mGlu receptors modulate the multiple forms of synaptic plasticity at both SC-CA1 and MF synapses and allosteric modulators of mGlu receptors have emerged as potential therapeutic agents that may rescue plasticity deficits and improve cognitive function in patients suffering from multiple neurological and psychiatric disorders.
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9 MeSH Terms
Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4).
Gogliotti RD, Blobaum AL, Morrison RM, Daniels JS, Salovich JM, Cheung YY, Rodriguez AL, Loch MT, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR
(2016) Bioorg Med Chem Lett 26: 2984-2987
MeSH Terms: Allosteric Regulation, Animals, Microsomes, Liver, Picolinic Acids, Pyrroles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Sulfonamides, Triazoles
Show Abstract · Added April 6, 2017
Herein we report the synthesis and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as novel positive allosteric modulators of mGlu4. We detail our work towards finding phenyl replacements for the core scaffold of previously reported phenyl sulfonamides and phenyl sulfone compounds. Our efforts culminated in the identification of N-(1-((3,4-dimethylphenyl)sulfonyl)-1H-pyrrol-3-yl)picolinamide as a potent PAM of mGlu4.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Discovery of 3-aminopicolinamides as metabotropic glutamate receptor subtype 4 (mGlu4) positive allosteric modulator warheads engendering CNS exposure and in vivo efficacy.
Gogliotti RD, Engers DW, Garcia-Barrantes PM, Panarese JD, Gentry PR, Blobaum AL, Morrison RD, Daniels JS, Thompson AD, Jones CK, Conn PJ, Niswender CM, Lindsley CW, Hopkins CR
(2016) Bioorg Med Chem Lett 26: 2915-2919
MeSH Terms: Allosteric Regulation, Amides, Animals, Central Nervous System, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Discovery, Humans, Molecular Structure, Picolines, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added April 6, 2017
This letter describes the further chemical optimization of the picolinamide-derived family of mGlu4 PAMs wherein we identified a 3-amino substituent to the picolinamide warhead that engendered potency, CNS penetration and in vivo efficacy. From this optimization campaign, VU0477886 emerged as a potent (EC50=95nM, 89% Glu Max) mGlu4 PAM with an attractive DMPK profile (brain:plasma Kp=1.3), rat CLp=4.0mL/min/kg, t1/2=3.7h) and robust efficacy in our standard preclinical Parkinson's disease model, haloperidol-induced catalepsy (HIC).
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.
Garcia-Barrantes PM, Cho HP, Starr TM, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 2289-92
MeSH Terms: Animals, Central Nervous System, Drug Discovery, Excitatory Amino Acid Antagonists, Humans, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added April 6, 2017
This letter describes the re-exploration of the mGlu1 PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu1 PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only ∼6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu5 PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and ∼3- to 4-fold improvement in CNS exposure (Kps 1.01-1.19); albeit, with a ∼3-fold diminution in mGlu1 PAM potency, yet comparable efficacy (∼5-fold leftward shift of the glutamate concentration-response curve at 10μM). Thus, this effort has provided additional CNS penetrant mGlu1 PAM tools in a different chemotype than the VU0486321 scaffold. These compounds will permit a better understanding of the pharmacology and therapeutic potential of selective mGlu1 activation, while highlighting the steep SAR challenges that can often be encountered in GPCR allosteric modulator discovery.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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8 MeSH Terms
N-Alkylpyrido[1',2':1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents.
Felts AS, Rodriguez AL, Morrison RD, Venable DF, Blobaum AL, Byers FW, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2016) Bioorg Med Chem Lett 26: 1894-900
MeSH Terms: Allosteric Regulation, Animals, Central Nervous System, Dose-Response Relationship, Drug, Male, Mice, Molecular Structure, Pyrazoles, Pyrimidines, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added April 6, 2017
Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.
Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 1869-72
MeSH Terms: Allosteric Regulation, Central Nervous System, Coumarins, Dose-Response Relationship, Drug, Drug Discovery, Drug Stability, Furans, Humans, Isoindoles, Molecular Structure, Phthalimides, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added April 6, 2017
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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14 MeSH Terms