Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain

Bennett, Chad; Burnett, Duane A.; Greenlee, William J.; Knutson, Chad; Korakas, Peter; Li, Cheng; Tulshian, Deen; Wu, Wen‐Lian; Bertorelli, Rosalia; Fredduzzi, Silva; Grilli, Mariagrazia; Lozza, Gianluca; Reggiani, Angelo; Veltri, Alessio

doi:10.1016/j.bmcl.2011.12.131

Cited by 20 publications

(6 citation statements)

References 11 publications

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“…Metabotropic glutamate receptors are known to modulate pain sensitivity ( Chiechio and Nicoletti, 2012 ; Palazzo et al, 2014 ; Chiechio, 2016 ). In particular analgesia can be obtained by either blocking group I mGlu receptors, namely mGlu1 and mGlu5 ( Walker et al, 2001 ; Sasikumar et al, 2010 ; Bennett et al, 2012 ; Brumfield et al, 2012 ) or by activating group II and group III mGlu receptors ( Chiechio and Nicoletti, 2012 ; Chiechio, 2016 ; Johnson et al, 2017 ). Also, we have demonstrated that epigenetic drugs that increase the expression of mGlu2 receptors are analgesic in models of persistent pain ( Chiechio et al, 2002 , 2009 , 2010 ; Zammataro et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice

et al. 2017

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Gender and sex differences in pain recognition and drug responses have been reported in clinical trials and experimental models of pain. Among antidepressants, contradictory results have been observed in patients treated with selective serotonin reuptake inhibitors (SSRIs). This study evaluated sex differences in response to the SSRI fluoxetine after chronic administration in the mouse formalin test. Adult male and female CD1 mice were intraperitoneally injected with fluoxetine (10 mg/kg) for 21 days and subjected to pain assessment. Fluoxetine treatment reduced the second phase of the formalin test only in female mice without producing behavioral changes in males. We also observed that fluoxetine was able to specifically increase the expression of metabotropic glutamate receptor type-2 (mGlu2) in females. Also a reduced expression of the epigenetic modifying enzyme, histone deacetylase 2 (HDAC2), in dorsal root ganglia (DRG) and dorsal horn (DH) together with an increase histone 3 acetylation (H3) level was observed in females but not in males. With this study we provide evidence that fluoxetine induces sex specific changes in HDAC2 and mGlu2 expression in the DH of the spinal cord and in DRGs and suggests a molecular explanation for the analgesic effects in female mice.

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Section: Discussionmentioning

confidence: 99%

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice

et al. 2017

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“…A better understanding of whether different opiate molecules affect molecular and cellular aspects of ahNG may also help designing and developing novel analgesic drugs for chronic pain states. Several drugs acting at different targets are under development for chronic pain treatment (Sasikumar et al, 2010; Bennett et al, 2012; Chang et al, 2015; Yaksh et al, 2015). We propose that future drug design should take into consideration the development of powerful analgesics that, by preserving ahNG, may also protect cognitive functions and counteract mood alterations which often represent comorbidities in chronic pain states.…”

Section: Clinical Implications and Long-term Perspectivesmentioning

confidence: 99%

Opiate Analgesics as Negative Modulators of Adult Hippocampal Neurogenesis: Potential Implications in Clinical Practice

Bortolotto

Grilli

2017

Front. Pharmacol.

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During the past decade, studies of the mechanisms and functional implications of adult hippocampal neurogenesis (ahNG) have significantly progressed. At present, it is proposed that adult born neurons may contribute to a variety of hippocampal-related functions, including specific cognitive aspects and mood regulation. Several groups focussed on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells (NSC/NPC), including clinically relevant drugs. Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Since that initial report, a vast array of information has been collected on the effect of opiate drugs, by either modulating proliferation of stem/progenitor cells or interfering with differentiation, maturation and survival of adult born neurons. The goal of this review is to critically revise the present state of knowledge on the effect of opiate drugs on the different developmental stages of ahNG, as well as the possible underlying mechanisms. We will also highlight the potential impact of deregulated hippocampal neurogenesis on patients undergoing chronic opiate treatment. Finally, we will discuss the differences in the negative impact on ahNG among clinically relevant opiate drugs, an aspect that may be potentially taken into account to avoid long-term deregulation of neural plasticity and its associated functions in the clinical practice.

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“…mGlu 1 knockout mice show decreased pain sensitivity (Schkeryantz et al, 2007) and administration of the mGlu 1 -selective NAM JNJ16259685 (Lavreysen et al, 2004) is reported to show efficacy in a rodent neuropathic pain model (formalin hyperalgesia) (Mabire et al, 2005). Additionally, mGlu 1 -selective antagonists showed in vivo activity in the spinal nerve ligation test (Bennett et al, 2012). Taken together, the development of mGlu 1 -selective NAMs (Annoura H, 1996; Mabire et al, 2005) and efficacy in preclinical models are promising for the potential treatment of neuropathic pain.…”

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Development of allosteric modulators of GPCRs for treatment of CNS disorders

Nickols

Conn

2014

Neurobiology of Disease

202

154

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The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than do orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as “bitopic” ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.

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Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain

Cited by 20 publications

References 11 publications

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice

Opiate Analgesics as Negative Modulators of Adult Hippocampal Neurogenesis: Potential Implications in Clinical Practice

Development of allosteric modulators of GPCRs for treatment of CNS disorders

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