Understanding Exposure-Receptor Occupancy Relationships for Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators across a Range of Preclinical and Clinical Studies

Bennett, K.A.; Sergeev, Eugenia; MacSweeney, Cliona; Bakker, Geor; Cooper, Anne

doi:10.1124/jpet.120.000371

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…Future studies are needed to determine how these GluR genes contribute to substance involvement. It is encouraging that the GRM5/mGluR5‐specific negative allosteric modulator HTL0014242 (now called TMP‐301) has been approved to enter phase I clinical trials for the treatment of alcohol and other substance disorders 49 . Ach receptors, which may excite or inhibit target cells, can be either nicotinic or muscarinic receptors.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the brain transcriptome for substance‐associated genes: An update on large‐scale genome‐wide association studies

Zhao,

Han,

Zheng

2023

Addiction Biology

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Substance use disorder (SUD) arises from the initiation to subsequent regular, irregular and harmful use of substances such as alcohol, tobacco/nicotine and cannabis. While thousands of genetic variants have been identified from recent large‐scale genome‐wide association studies (GWAS), understanding their functions in substance involvement and investigating the mechanisms by which they act in the addiction circuits remains challenging. In this study, we re‐analysed the brain regional transcriptome data from the most comprehensive postmortem transcriptomic study, with a focus on up‐ or down‐regulation of substance‐associated protein‐coding genes in the addiction circuit‐related brain regions (AddictRegions), including six cortical and 11 subcortical regions. We found that substance‐associated genes were overrepresented in AddictRegions. Interestingly, we observed a greater degree of genetic overlap between initiation and use and between use and SUD than between initiation and SUD. Moreover, substance initiation, use and SUD‐associated genes tend to shift their enriched AddictRegions from the cortical for initiation and, to a lesser extent, substance use to subcortical regions for SUD (e.g., thalamus, substantia nigra and ventral tegmental area). We also uncovered a pattern of coordinated cortical up‐regulation and subcortical down‐regulation for the genes associated with tobacco initiation and alcohol use. Moreover, the Gene Ontology terms of glutamate receptor activity and neurotransmitter binding were most significantly overrepresented in AddictRegion‐upregulated, substance‐associated genes, with the strongest enrichment for those involved in common substance use behaviours. Overall, our analysis provides a resource of AddictRegion‐related transcriptomes for studying substance‐associated genes and generates intriguing insights into the genetic control of substance initiation, use and SUD.

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Section: Discussionmentioning

confidence: 99%

Analysis of the brain transcriptome for substance‐associated genes: An update on large‐scale genome‐wide association studies

Zhao,

Han,

Zheng

2023

Addiction Biology

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“…Thus, pulsatile rather than sustained inhibition of mGluR5 might have durable therapeutic efficacy while avoiding maladaptive treatment resistance. We note that there are considerable differences in the pharmacokinetic properties of mGluR5 NAMs that have advanced to human studies, with affinities that range over 200-fold ( 54 ). In published FXS trials, mavoglurant (AFQ056), with a half-life of ~12 h ( 55 ), was dosed twice daily for 12 weeks ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

et al. 2021

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Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

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“…Thus, pulsatile rather than sustained inhibition of mGluR5 might have durable therapeutic efficacy while avoiding maladaptive treatment resistance. We note that there are considerable differences in the pharmacokinetic properties of mGluR5 NAMs that have advanced to human studies, with affinities that range over 200-fold [54]. In published FXS trials, mavoglurant (AFQ056), with a half-life of ~12 hours [55], was dosed twice daily for 12 weeks [26].…”

Section: Discussionmentioning

confidence: 99%

mGluR5 Negative Modulators for Fragile X: Resistance and Persistence

McCamphill

et al. 2021

Preprint

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Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (tolerance) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

show abstract

Understanding Exposure-Receptor Occupancy Relationships for Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators across a Range of Preclinical and Clinical Studies

Cited by 3 publications

References 44 publications

Analysis of the brain transcriptome for substance‐associated genes: An update on large‐scale genome‐wide association studies

Analysis of the brain transcriptome for substance‐associated genes: An update on large‐scale genome‐wide association studies

mGluR5 Negative Modulators for Fragile X: Treatment Resistance and Persistence

mGluR5 Negative Modulators for Fragile X: Resistance and Persistence

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