LY379268 / Eli Lilly - LARVOL DELTA

LY379268 and cariprazine but not donepezil differentially recover alterations in spontaneous oscillations, gamma-band auditory steady-state response and MMN caused by MK-801 in a rat EEG study: relevance for schizophrenia drug development (Neuroscience 2025) - "Their effects on MMN are also described. These results highlight glutamatergic as well as dopaminergic and serotoninergic systems as interesting targets to recover cortical excitation/inhibition balance in SZ."

Late-breaking abstract • Preclinical • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

mGluR2/3 receptor agonist LY379268 alleviates PTSD-like fear memories by downregulating the CaMKII/CREB signaling pathway in the hippocampus and prefrontal cortex. (PubMed, Neuroscience) - "Propranolol, a β-adrenergic antagonist, similarly influences fear memory through synaptic signaling in stress-responsive brain regions. However, treatment with 6 μM LY379268 improved these conditions, restoring CaMKII, ERK, CREB levels, and synaptic structure. This suggests that LY379268 may influence memory related to anxiety and stress in PTSD by modulating synaptic plasticity through the CaMKII/CREB pathway, providing a basis for further investigation into the underlying neurobiological mechanisms."

Journal • CNS Disorders • Depression • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Triggered temptations: A new procedure to compare reward-seeking behaviour induced by discriminative and conditioned stimuli in rats. (PubMed, Psychopharmacology (Berl)) - "Our new trial-based procedure can be used to identify unique and similar mechanisms underlying DS and CS influences on appetitive behaviour."

Journal • Preclinical

Group II metabotropic glutamate receptors modulate blood brain barrier function: direct and indirect effect through astrocytes and microglia. (PubMed, Eur J Pharmacol) - "Accordingly, LY379268 dampened T&I-induced expression of inflammatory cytokines in microglia cells, and again, co-treatment with VU6001966 contrasted this action. Thus, activation of mGlu2 and mGlu3 receptors preserves BBB functions acting directly on endothelial cells and contrasting the inflammatory response of astrocytes and microglia."

Journal • Oncology • IFNG • TNFA

Activating Group II Metabotropic Glutamate Receptors in the Basolateral Amygdala Inhibits Increases in Reward Seeking Triggered by Discriminative Stimuli in Rats. (PubMed, Int J Neuropsychopharmacol) - "Using a new procedure to test reward seeking induced by DSs and CSs, we show that BLA mGlu2/3 receptor activity mediates the conditioned incentive motivational effects of reward-predictive DSs."

Journal • Preclinical

Ibogalogs decrease neuropathic pain in mice through a mechanism involving crosstalk between 5-HT2A and mGlu2 receptors. (PubMed, Biomed Pharmacother) - "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."

Journal • Preclinical • Neuralgia • Pain

Prefrontal electrophysiological biomarkers and mechanism-based drug effects in a rat model of alcohol addiction. (PubMed, Transl Psychiatry) - "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."

Biomarker • Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

The auditory steady-state response as a translatable EEG biomarker is sensitive to the state of arousal in a rodent model (Neuroscience 2024) - "In addition, a mGluR2/3 agonist (LY-379268) was administered prior to initiation of ASSR recordings.The amplitude and phase precision (ITC) of the ASSR were increased during low arousal state (ínactive cycle) compared to the high arousal condition (active cycle)...The modulation of ASSR amplitude and ITC by arousal states warrants caution when investigating oscillatory brain activity and interpreting treatment effects in animal models. It also emphasizes the necessity of standardized EEG recording procedures in preclinical research."

Late-breaking abstract • Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β. (PubMed, Neurochem Int) - "Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist β-NAAG...These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1β. mGluR Ⅱ may be potential targets for drug development and clinical treatment of neuropathological pain."

Journal • Oncology • Pain • IL1B • TNFA

The Role of the Basolateral Amygdala in Reward-Seeking Evoked by Sucrose-Predictive Discriminative and Conditioned Stimuli in Female and Male Rats (CPDD 2024) - "Thus, across the sexes, the BLA mediates reward-seeking controlled by both CSs and DSs, implicating BLA neurons in distinct forms of cue-controlled reward-seeking behaviour."

Preclinical • CNS Disorders • Psychiatry

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, Curr Issues Mol Biol) - "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."

Journal • Preclinical • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HTR-Mediated G Signaling Pathway. (PubMed, Neurochem Res) - "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 A mutant), DOM-induced cAMP level was not regulated by LY354740, but was significantly enhanced by LY341495. The 5-HTR/mGluR2 heterodimers is critical for DOM-induced HTR and cAMP level, both of which are inhibited by mGluR2 agonists and enhanced by mGluR2 inverse agonists."

Journal

Reversal of mechanical hypersensitivity in mice by (2R,6R)-hydroxynorketamine (HNK) requires activation of group 2 metabotropic glutamate receptors (Neuroscience 2023) - "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."

Preclinical • CNS Disorders • Pain

The mGlu2/3 agonist LY379268 reduces sucrose taking, seeking, and motivation in male and female rats. (PubMed, Behav Pharmacol) - "The sucrose anti-taking, -seeking, and -motivation effects of LY379268 across male and female rats support further evaluation of glutamate modulation as an antiaddiction pharmacotherapy."

Journal • Preclinical • CNS Disorders • Psychiatry

Effects of the mGlu2/3 receptor agonist LY379268 on two models of disturbed auditory evoked brain oscillations in mice. (PubMed, Transl Psychiatry) - "In this study, we used two approaches to impair early sensory processing and cortical oscillations in mice: a pharmacological model targeting NMDA receptor function in the whole brain via systemic MK-801 application and an optogenetic model targeting parvalbumin-positive (PV+) interneurons locally in the medial prefrontal cortex (mPFC). 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."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Metabotropic glutamate group II receptor activation in the ventrolateral dorsal striatum suppresses incentive motivation for cocaine in rats. (PubMed, Psychopharmacology (Berl)) - "These results suggest that mGlu receptor activation in the ventrolateral dorsal striatum suppresses incentive motivation for cocaine, and this holds promise for new treatments to manage substance use disorder."

Journal • Preclinical • CNS Disorders • Psychiatry

In-vivo pharmacological imaging of NMDAR-modulators in rodents: functional ultrasound and MRI. (Neuroscience 2022) - "Multiple phMRI studies demonstrated high utility of the ketamine model as imaging platform to study pharmacological modulation of BOLD or rCBV responses by various classes of test compounds in rodents (Shim et al., 2021, Chin et al, 2011).Aim of this work was to prove the utility and value of the fUS imaging in preclinical drug discovery in mice using the ketamine model with known positive control compound - LY379268, a selective agonist of the group II glutamate receptors (mGluR2/3) and compare it to phMRI in rats.The fUS experiments were performed on total of 36 naïve C57Bl/6J males, 8-10 weeks old mice with dexmedetomidine anesthesia. 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,..."

Preclinical • CNS Disorders • Psychiatry • Schizophrenia • FUS

mGlur2 and mGluR3 activation mediate different neuronal and synaptic functions of CeA neurons in an arthritis pain model (Neuroscience 2022) - "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."

CNS Disorders • Musculoskeletal Pain • Pain • GFAP

Amygdala mGluR2 and mGluR3 modulate different aspects of arthritis pain-related behaviors (Neuroscience 2022) - "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."

CNS Disorders • Mental Retardation • Mood Disorders • Musculoskeletal Pain • Pain • Psychiatry

Projection Specific Effects of mGlu3 Receptor Activation in Regulation of Schizophrenia-Like Nucleus Accumbens Pathophysiology and Sociability Deficits (ACNP 2022) - "The mGlu3 receptor signaling was activated by bath application of mGlu2/3 receptor agonist, LY379268 in the presence of mGlu2 negative allosteric modulators... These data demonstrate that activation of mGlu3 receptors can rescue schizophrenia-like physiological and behavioral deficits and provide a mechanism by which polymorphisms in the GRM3 can contribute to the pathophysiology of schizophrenia. Therefore, targeting these receptors can provide a viable approach for developing new therapeutics for treating patients with schizophrenia."

CNS Disorders • Depression • Psychiatry • Schizophrenia

Presynaptic 5-HT-mGlu2/3 Receptor-Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis. (PubMed, Cells) - "5-HT receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. 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."

Journal • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Expression of group II and III mGluRs in the carotid body and its role in the carotid chemoreceptor response to acute hypoxia. (PubMed, Front Physiol) - "We found that LY379268 and L-SOP inhibited hypoxia-induced enhancement of CSN activity. Based on the above findings, group II and III mGluRs appear to play an inhibitory role in the carotid chemoreceptor response to acute hypoxia."

Journal • GRM8

mGlu2 mechanism-based interventions to treat alcohol relapse. (PubMed, Front Pharmacol) - "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."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry

Metabotropic glutamate receptors modulate exocytotic tau release and propagation. (PubMed, J Pharmacol Exp Ther) - "In all mouse and human synaptosomal preparations, tau release was inhibited by the selective mGlu2/3 receptor 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."

Journal • Alzheimer's Disease • CNS Disorders

Group II Metabotropic Glutamate Receptors Reduce Apoptosis and Regulate BDNF and GDNF Levels in Hypoxic-Ischemic Injury in Neonatal Rats. (PubMed, Int J Mol Sci) - "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."

IO biomarker • Journal • Preclinical • Cardiovascular • CNS Disorders • Vascular Neurology • BAX • BCL2 • BDNF • HIF1A