Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity

Anighoro, Andrew; Graziani, Davide; Bettinelli, Ilaria; Cilia, Antonio; Toma, Carlo De; Longhi, Matteo; Mangiarotti, F; Menegon, Sergio; Pirona, Lorenza; Poggesi, Elena; Riva, Carlo Ruga; Rastelli, Giulio

doi:10.1016/j.bmc.2015.05.008

Cited by 15 publications

(26 citation statements)

References 45 publications

(101 reference statements)

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“…screened for putative receptor ligands. This approach has been successfully used to identify novel ligands with unique structures that bind to a given receptor, such as antagonists to melanin-concentrating hormone receptor 1 (Cavasotto et al, 2008) and allosteric modulators of mGluR5 (Anighoro et al, 2015). Thus, the crystal structure of a receptor or the homology model of a receptor based on the crystal structure of a closely related receptor can be used to identify ligands by virtual screening (Stockert and Devi, 2015).…”

Section: Discussionmentioning

confidence: 99%

The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning

Bobeck

Gomes

Pena

et al. 2017

Neuropsychopharmacol.

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Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits, MS0021570_1, was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells, (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons, and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus. The role of GPR171 in anxiety-like behavior or fear conditioning was evaluated following systemic or intra-BLA administration of MS0021570_1, as well as following lentiviral-mediated knockdown of GPR171 in the BLA. We find that systemic administration of MS0021570_1 attenuates anxiety-like behavior while intra-BLA administration or knockdown of GPR171 in the BLA reduces anxiety-like behavior and fear conditioning. These results indicate that the BigLEN-GPR171 system plays an important role in these behaviors and could be a novel target to develop therapeutics to treat psychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning

Bobeck

Gomes

Pena

et al. 2017

Neuropsychopharmacol.

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“…Other highly potent and selective mGluR5 NAMs, such as fenobam ( Pecknold et al, 1982 ; Porter et al, 2005 ; Berry-Kravis et al, 2009 ), mavoglurant ( Kumar et al, 2013 ; Stocchi et al, 2013 ; Reilmann et al, 2015 ), ADX10059, AZD2066 ( Keywood et al, 2009 ; Zerbib et al, 2010 , 2011 ; Rohof et al, 2012 ), and AZD9272 ( Kalliomaki et al, 2013 ), have been investigated in humans for different indications and could find application in the treatment of addiction if their pharmacokinetics and side effect profiles prove favorable. Moreover, the industry continuously develops new compounds ( Felts et al, 2009 ; Emmitte, 2011 ; Kaae et al, 2012 ; Keck et al, 2012 ; Molck et al, 2012 , 2014 ; Anighoro et al, 2015 ; Jaeschke et al, 2015 ; Lindemann et al, 2015 ) and new mGluR5-specific PET tracers ( Yu, 2007 ; Mu et al, 2010 ; Sobrio, 2013 ), such as [18F]PSS232 ( Sephton et al, 2015 ) and [18F]FPEB ( Lim et al, 2014 ). These developments will inspire new preclinical and clinical research, which can build on the findings reported here by focusing on dose / receptor occupancy ranges that could more directly be translated to the clinic ( Markou et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Negative Allosteric Modulators of Metabotropic Glutamate Receptors Subtype 5 in Addiction: a Therapeutic Window

Mihov

Hasler

2016

IJNPPY

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Background:Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic.Methods:Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats.Results:MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window.Conclusion:Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders.

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“…Along the same lines, a medicinal chemistry study by Anighoro et al [65] used an homology model of mGlu 5 based on the crystal structure of mGlu 1 . Docking of MPEP and fenobam (mGlu 5 NAMs) was performed using an induced fit approach.…”

Section: Group I Mglu Receptorsmentioning

confidence: 99%

Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors

2019

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Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular and 7-transmembrane domains have played an important role to enable structure-based modeling approaches, whilst we also discuss the successful application of ligand-based methods. We summarize the literature and highlight the areas where modeling and experiment have delivered important understanding for mGlu receptor drug discovery. Finally, we offer suggestions of future areas of opportunity for computational work.

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Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity

Cited by 15 publications

References 45 publications

The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning

The BigLEN-GPR171 Peptide Receptor System Within the Basolateral Amygdala Regulates Anxiety-Like Behavior and Contextual Fear Conditioning

Negative Allosteric Modulators of Metabotropic Glutamate Receptors Subtype 5 in Addiction: a Therapeutic Window

Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors

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