- |||||||||| oxaliplatin / Generic mfg., LY379268 / Eli Lilly
Preclinical, Journal: Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT2A and mGlu2 receptors. (Pubmed Central) - Mar 2, 2025
The objective of this study was to determine the anti-neuropathic activity of a variety of ibogalogs, including tabernanthalog (TBG), ibogaminalog (DM506), ibogainalog (IBG), nor-IBG, catharanthalog (CAG), and PNU-22394 using the oxaliplatin (OXA) neuropathic pain model in mice, and to investigate whether there is crosstalk between the 5-HT2A and mGlu2 receptors...Sub-threshold doses of IBG (1?mg/kg) and nor-IBG (3?mg/kg) produced pain relief only in the presence of a sub-threshold dose of LY379268, a selective mGlu2 receptor agonist, indicating that signaling through both 5-HT2A and mGlu2 receptors improves efficacy...Ibogalogs increased mGlu2 receptor phosphorylation on Ser843, a proposed key molecular event underlying the functional receptor crosstalk. Our study shows for the first time that diverse ibogalogs induce anti-neuropathic activity through a synergic mechanism involving both 5-HT2A and mGlu2 receptors.
- |||||||||| LY379268 / Eli Lilly
Biomarker, Preclinical, Journal: Prefrontal electrophysiological biomarkers and mechanism-based drug effects in a rat model of alcohol addiction. (Pubmed Central) - Dec 6, 2024
We monitored neural oscillations and event-related potentials in awake alcohol-dependent rats during abstinence and following treatment with psilocybin or LY379268, agonists of the serotonin 2A receptor (5-HT2AR), and the metabotropic glutamate receptor 2 (mGluR2), that are known to reduce prefrontal dysfunction and relapse...Furthermore, alcohol-dependent animals displayed a dominance in higher beta frequencies indicative of a state of hyperarousal that is prone to relapse, which particularly psilocybin was able to counteract. In summary, we provide prefrontal markers indicative of relapse and treatment response, especially for psychedelic drugs.
- |||||||||| LY379268 / Eli Lilly
Preclinical, Journal: Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line. (Pubmed Central) - Jan 22, 2024
In the study, LY 379268 (agonist) and JNJ-46281222 (positive allosteric modulator; PAM) were used as control reference molecules...Therefore, our study not only emphasizes the positive effects of this compound on cell viability against Glu toxicity but also sheds light on the potential of THRX-195518, acting as a mGlu2 PAM, based on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) data, as a candidate drug molecule. These findings underscore the potential utility of THRX-195518 against both neurotoxicity and Central Nervous System (CNS) disorders, providing valuable insights.
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Journal: Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HTR-Mediated G Signaling Pathway. (Pubmed Central) - Nov 22, 2023
These findings underscore the potential utility of THRX-195518 against both neurotoxicity and Central Nervous System (CNS) disorders, providing valuable insights. In order to investigate the effects of mGluR2 agonists and inverse agonists on hallucinogenic 5-HTR agonists DOM-induced HTR, C57BL/6 mice were pretreated with mGluR2 agonists (LY379268, LY354740, LY404039) or the inverse agonist LY341495, and the HTR was manually counted after administering DOM immediately...In HEK-293T cells co-expressing 5-HTR and mGluR2 A677S/A681P/A685G mutant (mGluR2 3
- |||||||||| LY379268 / Eli Lilly
Reversal of mechanical hypersensitivity in mice by (2R,6R)-hydroxynorketamine (HNK) requires activation of group 2 metabotropic glutamate receptors (WCC Halls A-C) - Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_4826;
This study evaluated the contribution of Group 2 metabotropic glutamate receptors (mGlu2 and mGlu3) to alter HNK-mediated reversal of mechanical hypersensitivity in a murine inflammatory pain model with either a selective mGlu2/3R agonist LY379268 (LY68), or an mGlu2R negative allosteric modulator, VU6001966 (VU66)...0362), with mean return to baseline values of 45% in Vehicle/HNK animals compared to VU66/HNK mice at 25%. These data support the hypothesis that mGluR2s may contribute to HNK's analgesic action.
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Preclinical, Journal: Effects of the mGlu2/3 receptor agonist LY379268 on two models of disturbed auditory evoked brain oscillations in mice. (Pubmed Central) - May 10, 2023
Single neuron recordings revealed a strong effect of LY379268 on the signal-to-noise ratio during auditory stimulation and optogenetic inhibition of PV+ interneurons. Our results contribute to a better understanding of how group II metabotropic glutamate receptors modulate neuronal population and network activity under sensory stimulation while challenged pharmacologically or optogenetically.
- |||||||||| LY379268 / Eli Lilly
Journal: Presynaptic 5-HT-mGlu2/3 Receptor-Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis. (Pubmed Central) - Oct 22, 2022
Clozapine (0.1-10 μM) mimics the 5-HT agonist (±) DOI and inhibits the KCl-evoked [H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect...In conclusion, 5-HT and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens.
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Journal: Metabotropic glutamate receptors modulate exocytotic tau release and propagation. (Pubmed Central) - Oct 12, 2022
In all mouse and human synaptosomal preparations, tau release was inhibited by the selective metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268, an effect prevented by the selective mGlu2/3 antagonist LY341495...In this paper we describe the role of regulated exocytosis, and the SNARE protein SNAP25, in mediating tau release from rodent and human synaptosomes. We also show that a selective mGluR2/3 agonist is highly effective in blocking tau release from synaptosomes and tau propagation between neurons, opening the way to the discovery of novel therapeutic approaches to this devastating disease.
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In-vivo pharmacological imaging of NMDAR-modulators in rodents: functional ultrasound and MRI. (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_3830;
The LY379268 fully and highly significantly (p<0.01, pointwise one-way ANOVA) reversed the 30 mg/kg ketamine effect in all brain regions, including amygdala.In summary, our results show great applicability of fUS - ketamine platform for in vivo drug testing of novel psychoactive compounds, such as allosteric modulators, co-agonists and other pharmacological classes targeting glutamatergic system. Compared to phMRI, fUS imaging is a completely non-invasive, high-sensitivity measurement with shorter protocol, which increases success rate and enables repeated measurements in lightly anesthetized mice while producing similar deliverables (rCBV maps, response profile and its derivatives).
- |||||||||| LY379268 / Eli Lilly
Amygdala mGluR2 and mGluR3 modulate different aspects of arthritis pain-related behaviors (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_1806;
The following drugs were stereotaxically administered by microdialysis into the CeA of arthritic rats: a group II agonist (LY379268), a PAM selective for mGluR2 (LY487379) or a combination of a group II mGluR agonist (LY379268) with a NAM selective for mGluR2 (VU6001966)...Both subtypes are involved in the beneficial effects of group II mGluRs on emotional-affective responses (vocalizations) in arthritis pain. The data identify distinct roles of mGluR2 and mGluR3 in amygdala (CeA) in different aspects of pain modulation, which may guide subtype-selective therapeutic strategies.
- |||||||||| LY379268 / Eli Lilly
mGlur2 and mGluR3 activation mediate different neuronal and synaptic functions of CeA neurons in an arthritis pain model (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_1801;
Brain slice physiology was performed to determine the effects of a group II mGluR agonist (LY379268) alone or in combination with a mGluR2 selective NAM (VU6001966) to activate mGluR3, and of an mGluR2 selective PAM (LY487379) on CeA neurons...The results suggest that mGluR2 and mGluR3 modulate CeA functions in pain differently and that glial-neuronal interaction mediated by astrocytic mGluR3 plays a critical role in amygdala pain mechanisms. These new insights into neuronal and non-neuronal mGluR function in the amygdala may help identify appropriate therapeutic strategies for pain management.
- |||||||||| LY379268 / Eli Lilly
Journal: mGlu2 mechanism-based interventions to treat alcohol relapse. (Pubmed Central) - Oct 4, 2022
Two mGlu2/3 agonists, LY379268 and LY354740 (a structural analog of LY379268 six-fold more potent in activating mGlu2 over mGluR3), were tested in a well-established rat model of relapse, the alcohol deprivation effect (ADE) with repeated deprivation phases...Combination treatment of mGlu2/3 agonist and PAM had similar effect on relapse-like drinking to that seen in mGlu2/3 agonist treatment alone. Together with other preclinical data showing that PAMs can reduce alcohol-seeking behavior we conclude that mGlu2 PAMs should be considered for clinical trials in alcohol-dependent patients.
- |||||||||| LY379268 / Eli Lilly
Preclinical, Journal, IO biomarker: Group II Metabotropic Glutamate Receptors Reduce Apoptosis and Regulate BDNF and GDNF Levels in Hypoxic-Ischemic Injury in Neonatal Rats. (Pubmed Central) - Jul 17, 2022
The effects of intraperitoneal application of mGluR2 agonist LY379268 (5 mg/kg) and the specific mGluR3 agonist NAAG (5 mg/kg) (1 h or 6 h after HI) on apoptotic processes and initiation of the neuroprotective mechanism were investigated...Our results show that activation of mGluR2/3 receptors shortly after HI prevents brain damage by the inhibition of excessive glutamate release and apoptotic damage decrease. mGluR2 and mGluR3 agonists produced comparable results, indicating that both receptors may be a potential target for early treatment in neonatal HI.
- |||||||||| LY379268 / Eli Lilly
The mGluR2 agonist LY379268 reduces sucrose taking, seeking, and motivation in male and female rats (Virtual Only) - Dec 20, 2021 - Abstract #Neuroscience2021Neuroscience_6773;
These findings replicate previous findings of sex differences in sucrose taking, seeking, and motivation. The generality of the anti-taking, -seeking, and -motivation effects of LY379268 across male and female rats support further evaluation of this and other compounds that modulate synaptic glutamate as potential anti-addiction pharmacotherapies.; Grant Support: DA016285-05; State of Washington
- |||||||||| LY379268 / Eli Lilly
Preclinical, Journal: Chronic stimulation of group II metabotropic glutamate receptors in the medulla oblongata attenuates hypertension development in spontaneously hypertensive rats. (Pubmed Central) - Oct 22, 2021
Compared with that in the sham control group, chronic LY379268 application (mGluR2/3 agonist; 0.40 μg/day) to the dorsal medulla oblongata for 6 weeks reduced the progression of hypertension in 6-week-old SHRs as indicated by the 40 mmHg reduction in systolic blood pressure and promoted their parasympathetic nervous activity as evidenced by the heart rate variability...The mRNA expression level of mGluR2, but not mGluR3, in the dorsal medulla oblongata was substantially reduced in SHRs compared to that of the control strain. In conclusion, mGluR2/3 signaling might be responsible for hypertension development in SHRs, and modulating mGluR2/3 expression/stimulation in the dorsal brainstem could be a novel therapeutic strategy for hypertension via increasing the parasympathetic activity.
- |||||||||| LY379268 / Eli Lilly
Journal: Metabotropic group II glutamate receptors in the basolateral amygdala mediate cue-triggered increases in incentive motivation. (Pubmed Central) - Oct 20, 2021
In conclusion, mGluR2/3 signaling might be responsible for hypertension development in SHRs, and modulating mGluR2/3 expression/stimulation in the dorsal brainstem could be a novel therapeutic strategy for hypertension via increasing the parasympathetic activity. mGlu receptor activity in the BLA mediates cue-triggered potentiation of incentive motivation for reward, suppressing both cue-induced increases in instrumental pursuit of the reward and anticipatory approach behaviour.
- |||||||||| LY379268 / Eli Lilly
Preclinical, Journal: Antioxidant and neuroprotective effects of mGlu3 receptor activation on astrocytes aged in vitro. (Pubmed Central) - Sep 4, 2021
Our study aimed to determine whether LY379268, an mGlu3R agonist, exerts an antioxidant effect on aged cultured rat astrocytes...We conclude that activation of mGlu3R in aged astrocytes had an anti-oxidant effect and protected hippocampal neurons against Aβ-induced neurotoxicity. The present study suggests mGlu3R activation in aging astrocytes as a therapeutic strategy to slow down age-associated neurodegeneration.
- |||||||||| LY379268 / Eli Lilly
Preclinical, Journal, IO biomarker: Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia-Ischemia in Neonatal Rat Brains. (Pubmed Central) - May 20, 2021
The application of agonists of mGluR3 (N-acetylaspartylglutamate; NAAG) or mGluR2 (LY379268) inhibits the release of glutamate and reduces neurodegeneration in a neonatal rat model of HI, although the exact mechanism is not fully recognized...Based on the data presented in this study and on our previous findings, we conclude that the neuroprotective effect of NAAG applied 1 h before HI is most likely the result of a combination of mGluR3 and NMDA receptor activation, whereas the beneficial effects of NAAG pretreatment 24 h before HI can be explained by the activation of NMDA receptors and induction of the antioxidative/antiapoptotic defense system triggered by mild excitotoxicity in neurons. This response to NAAG pretreatment is consistent with the commonly accepted mechanism of preconditioning.
- |||||||||| LY379268 / Eli Lilly
Journal: Unraveling the β-AMYLOID clearance by astrocytes: Involvement of metabotropic glutamate receptor 3, sAPPα, and class-A scavenger receptor. (Pubmed Central) - Sep 5, 2020
Since we show that both sAPPα and the mGlu3R agonist LY379268 increased expression of class-A scavenger receptor (SR-A) in astrocytes, we next determined whether SR-A mediates mGlu3R- or sAPPα-induced Aβ uptake by using astrocyte cultures derived from SR-A knockout mice...We also show results of coimmunoprecipitation and functional assays offering evidence of possible heterotrimerization of sAPPα with Aβ and SR-A which could allow Aβ to enter the astrocyte. In conclusion the present paper describes a novel pathway for Aβ clearance by astrocytes involving sAPPα as an enhancer of SR-A-dependent Aβ phagocytosis.
- |||||||||| LY379268 / Eli Lilly
Journal: 5-HT receptor-dependent phosphorylation of mGlu receptor at Serine 843 promotes mGlu receptor-operated G signaling. (Pubmed Central) - May 7, 2020
Among the five mGlu receptor-phosphorylated residues identified in HEK-293 cells, the phosphorylation of Ser was enhanced upon mGlu receptor stimulation by the orthosteric agonist LY379268 only in cells co-expressing the 5-HT receptor...Mutation of Ser into alanine strongly reduced G signaling elicited by mGlu or 5-HT receptor stimulation in cells co-expressing both receptors. Collectively, these findings identify mGlu receptor phosphorylation at Ser as a key molecular event that underlies the functional crosstalk between both receptors.
- |||||||||| LY379268 / Eli Lilly, dizocilpine (MK801) / Merck (MSD)
Restoration of Translatable Eeg Deficits in an Acute Model for Schizophrenia-Linked Cortical Network Dysfunction by Positive Modulation of mGluR2 (Spadolini - Ground Floor) - Apr 4, 2020 - Abstract #SIRS2020SIRS_1232;
Moreover, we showed for the first time that an mGluR2/3 agonist as well as an mGluR2 PAM can restore 40Hz ASSR coherence deficits, reflecting a normalization of task-relevant gamma synchronization, crucial for cognitive function. Therefore, a selective allosteric modulator of the mGlu2 receptor could have utility as a novel approach for the treatment of neuropsychiatric disorders that are associated with altered glutamate transmission such as schizophrenia.
- |||||||||| LY379268 / Eli Lilly
Preclinical, Journal: Group II metabotropic glutamate receptor blockade promotes stress resilience in mice. (Pubmed Central) - Mar 18, 2020
Prophylactic treatment with the LY341495, both systemically and via microinjection into the medial prefrontal cortex (mPFC), up to 7 days before IES, prevented both the induction of escape deficits and their reinstatement by brief re-exposure to IES up to 20 days after treatment. Overall, blockade of mGlu enhanced stress resilience and deletion of mGlu, but not mGlu, conferred a stress-resilient phenotype, indicating that prophylactic treatments reducing mGlu activity may protect against stress-induced changes underlying the development or recurrence of stress-induced disorders, including depression.
- |||||||||| citalopram / Generic mfg., clozapine / Generic mfg.
Preclinical, Journal: A medium throughput rodent model of relapse from addiction with behavioral and pharmacological specificity. (Pubmed Central) - Mar 12, 2020
Other compounds including clozapine, d-amphetamine, chlordiazepoxide, ABT-431, naltrexone and citalopram were without effect...Drug effects demonstrated both behavioral and pharmacological specificity. The present experimental design thus allows for efficient and rapid assessment of the effects of drugs that might be useful in the treatment of addiction-associated relapse.
- |||||||||| LY379268 / Eli Lilly
Preclinical, Journal: Specific activation of mGlu2 induced IGF-1R transactivation in vitro through FAK phosphorylation. (Pubmed Central) - Sep 12, 2019
...To investigate whether there is any communication between mGlu2 and RTKs, we generated a CHO-mGlu2 cell line that stably expresses mGlu2 and showed that activation of mGlu2 by LY379268, a group II mGlu agonist, was able to transactivate insulin-like growth factor 1 receptor (IGF-1R)...In primary mouse cortical neurons, similar signaling pathways were observed when mGlu2 were stimulated by LY487379, an mGlu2 positive allosteric modulator. Transactivation of IGF-1R through FAK in response to mGlu2 should provide a better understanding of the association of mGlu2 with brain disease.
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