RESUMO
M4 muscarinic receptors are highly expressed in the striatum and cortex, brain regions that are involved in diseases such as Parkinson's disease, schizophrenia, and dystonia. Despite potential therapeutic advantages of specifically targeting the M4 receptor, it has been historically challenging to develop highly selective ligands, resulting in undesired off-target activity at other members of the muscarinic receptor family. Recently, we have reported first-in-class, potent, and selective M4 receptor antagonists. As an extension of that work, we now report the development and characterization of a radiolabeled M4 receptor antagonist, [3H]VU6013720, with high affinity (pKd of 9.5 ± 0.2 at rat M4, 9.7 at mouse M4, and 10 ± 0.1 at human M4 with atropine to define nonspecific binding) and no significant binding at the other muscarinic subtypes. Binding assays using this radioligand in rodent brain tissues demonstrate loss of specific binding in Chrm4 knockout animals. Dissociation kinetics experiments with various muscarinic ligands show differential effects on the dissociation of [3H]VU6013720 from M4 receptors, suggesting a binding site that is overlapping but may be distinct from the orthosteric site. Overall, these results demonstrate that [3H]VU6013720 is the first highly selective antagonist radioligand for the M4 receptor, representing a useful tool for studying the basic biology of M4 as well for the support of M4 receptor-based drug discovery. SIGNIFICANCE STATEMENT: This manuscript describes the development and characterization of a novel muscarinic (M) acetylcholine subtype 4 receptor antagonist radioligand, [3H]VU6013720. This ligand binds to or overlaps with the acetylcholine binding site, providing a highly selective radioligand for the M4 receptor that can be used to quantify M4 protein expression in vivo and probe the selective interactions of acetylcholine with M4 versus the other members of the muscarinic receptor family.
Assuntos
Acetilcolina , Receptores Muscarínicos , Ratos , Humanos , Camundongos , Animais , Acetilcolina/metabolismo , Receptores Muscarínicos/metabolismo , Receptor Muscarínico M4/metabolismo , Atropina , Ligantes , Colinérgicos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/metabolismo , Receptor Muscarínico M2/metabolismo , Ensaio Radioligante , Receptor Muscarínico M1/metabolismoRESUMO
This Letter details our efforts to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M4 receptor.
Assuntos
Descoberta de Drogas , Pirimidinas/farmacologia , Receptor Muscarínico M4/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
Stress can precipitate or worsen symptoms of many psychiatric disorders by dysregulating glutamatergic function within the prefrontal cortex (PFC). Previous studies suggest that antagonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) reduce stress-induced anhedonia through actions in the PFC, but the mechanisms by which these receptors act are not known. We now report that activation of mGlu3 induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala. Our data suggest mGlu3-LTD is mediated by postsynaptic AMPAR internalization in PFC pyramidal cells, and we observed a profound impairment in mGlu3-LTD following a single, 20-min restraint stress exposure. Finally, blocking mGlu3 activation in vivo prevented the stress-induced maladaptive changes to amydalo-cortical physiology and motivated behavior. These data demonstrate that mGlu3 mediates stress-induced physiological and behavioral impairments and further support the potential for mGlu3 modulation as a treatment for stress-related psychiatric disorders.
Assuntos
Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Aminoácidos , Tonsila do Cerebelo/fisiologia , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Células Piramidais/metabolismo , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologiaRESUMO
This Letter details our efforts to discover structurally unique M4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide core that provided improved M4 PAM activity and CNS penetration.
Assuntos
Imidazóis/química , Pirazinas/química , Receptor Muscarínico M4/química , Regulação Alostérica , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/metabolismo , Cinética , Ligação Proteica , Pirazinas/metabolismo , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter details our efforts to develop new M4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M4.
Assuntos
Piridazinas/química , Quinazolinas/química , Receptor Muscarínico M4/química , Triazóis/química , Regulação Alostérica , Animais , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Piridazinas/metabolismo , Piridazinas/farmacocinética , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Ratos , Receptor Muscarínico M4/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacocinéticaRESUMO
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M4 PAM activity and improved clearance and protein binding profiles.
Assuntos
Receptor Muscarínico M4/química , Regulação Alostérica , Amidas/química , Azetidinas/química , Benzeno/química , Estrutura Molecular , Ligação Proteica , Pirazinas/química , Piridinas/química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 2 Anéis/farmacologia , Isoquinolinas/farmacologia , Miotonina Proteína Quinase/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Isoquinolinas/química , Estrutura Molecular , Miotonina Proteína Quinase/metabolismo , Relação Estrutura-AtividadeRESUMO
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50â¯=â¯43â¯nM; AhR activationâ¯=â¯2.3-fold).
Assuntos
Indutores do Citocromo P-450 CYP1A2/farmacologia , Citocromo P-450 CYP1A2/biossíntese , Descoberta de Drogas , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Antiparkinsonianos/farmacologia , Indução Enzimática/efeitos dos fármacos , Humanos , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 PAMs to date, within the thieno[2,3-b]pyridine core, as the ß-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.
Assuntos
Amidas/química , Receptor Muscarínico M4/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/farmacocinética , Animais , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Ligação Proteica , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M4/química , Relação Estrutura-AtividadeRESUMO
This Letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent and selective, but not CNS penetrant. Potency was maintained, while CNS penetration was improved (rat brain:plasma Kp=0.74), within the original core after several rounds of optimization; however, the thieno[2,3-d]pyrimidine core was subject to extensive oxidative metabolism. Ultimately, we identified a 6-fluoroquinazoline core replacement that afforded good M4 PAM potency, muscarinic receptor subtype selectivity and CNS penetration (rat brain:plasma Kp>10). Moreover, this campaign provided fundamentally distinct M4 PAM chemotypes, greatly expanding the available structural diversity for this exciting CNS target.
Assuntos
Piperidinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Receptor Muscarínico M4/metabolismo , Tiofenos/farmacologia , Regulação Alostérica , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Quinazolinas/síntese química , Quinazolinas/metabolismo , Ratos , Receptor Muscarínico M4/agonistas , Receptor Muscarínico M4/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/metabolismoRESUMO
Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbß3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10µM).
Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Descoberta de Drogas , Indóis/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D4R) antagonists not previously reported as potential adjuvants for PD management. In this study, a library screening and artificial neural network quantitative structure-activity relationship (QSAR) modeling with experimentally driven library design resulted in a class of spirocyclic compounds to identify candidate D4R antagonists. However, developing selective D4R antagonists suitable for clinical translation remains a challenge.
Assuntos
Desenho Assistido por Computador , Relação Quantitativa Estrutura-Atividade , Humanos , Receptores de Dopamina D4/antagonistas & inibidores , Receptores de Dopamina D4/metabolismo , Compostos de Espiro/farmacologia , Compostos de Espiro/química , Antagonistas de Dopamina/farmacologia , Redes Neurais de Computação , Doença de Parkinson/tratamento farmacológico , Animais , Desenho de FármacosRESUMO
While the muscarinic acetylcholine receptor mAChR subtype 5 (M5) has been studied over decades, recent findings suggest that more in-depth research is required to elucidate a thorough understanding of its physiological function related to neurological and psychiatric disorders. Our efforts to identify potent, selective, and pharmaceutically favorable next-generation M5 antagonist tool compounds have led to the discovery of a novel triazolopyridine-based series. In particular, VU6036864 (45) showed exquisite potency (human M5 IC50 = 20 nM), good subtype selectivity (>500 fold selectivity against human M1-4), desirable brain exposure (Kp = 0.68, Kp,uu = 0.65), and high oral bioavailability (%F > 100%). VU6036864 (45) and its close analogues will support further studies of M5 as advanced antagonist tool compounds and play an important role in the emerging biology of M5.
RESUMO
This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10µM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30µM) and a robust 20-fold leftward shift of the ACh CRC.
Assuntos
Descoberta de Drogas , Indóis/farmacologia , Receptores Muscarínicos/metabolismo , Animais , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Hypoxia and ischemia are linked to several serious public health problems that affect most major organ systems. Specific examples include diseases of the cardiovascular, pulmonary, renal, neurologic, and musculoskeletal systems. The most significant pathway for cellular response to hypoxia is the hypoxia inducible factor (HIF) pathway. HIFs are transcription factors responsible for the activation of genes which encode proteins that mediate adaptive responses to reduced oxygen availability. A high-throughput cell-based HIF-mediated gene reporter screen was carried out using the NIH's Molecular Libraries Small Molecule Repository to identify activators of the HIF pathway. This communication describes the subsequent medicinal chemistry optimization of a triazine scaffold that led to the identification of the new molecular probe ML228. A discussion of HIF activation SAR within this chemotype as well as detailed in vitro characterization of the probe molecule is presented here.
Assuntos
Química Farmacêutica/métodos , Fator 1 Induzível por Hipóxia/metabolismo , Sondas Moleculares/farmacologia , Piridinas/síntese química , Triazinas/síntese química , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Hipóxia/tratamento farmacológico , Modelos Químicos , Conformação Molecular , Neovascularização Patológica , Estrutura Terciária de Proteína , Piridinas/farmacologia , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
A stressor can trigger lasting adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that may activate the metabotropic glutamate receptor 3 (mGlu3) to produce stress adaptations. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after, rats underwent context re-exposure, elevated zero maze (ZM), and acoustic startle (ASR) behavioral tests, followed by RT-PCR gene expression in the insular cortex and bed nucleus of the stria terminalis (BNST) to evaluate lasting behavioral and molecular adaptations from the stressor. Rats displayed stress-reactive behaviors in response to TMT exposure that were not affected by VU6010572. Freezing and hyperactivity were observed during the context re-exposure, and mGlu3-NAM pretreatment during stressor prevented the context freezing response. TMT exposure did not affect ZM or ASR measures, but VU6010572 increased time spent in the open arms of the ZM and ASR habituation regardless of stressor treatment. In the insular cortex, TMT exposure increased expression of mGlu (Grm3, Grm5) and NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) receptor transcripts, and mGlu3-NAM pretreatment blocked GriN3B upregulation. In the BNST, TMT exposure increased expression of GriN2B and GriN3B in vehicle-treated rats, but decreased expression in the mGlu3-NAM group. Similar to the insular cortex, mGlu3-NAM reversed the stressor-induced upregulation of GriN3B in the BNST. mGlu3-NAM also upregulated GriN2A, GriN2B, GriN3B and Grm2 in the control group, but not the TMT group. Together, these data implicate mGlu3 receptor signaling in some lasting adaptations of predator odor stressor and anxiolytic-like effects.
Assuntos
Adaptação Fisiológica/fisiologia , Comportamento Animal/fisiologia , Córtex Insular/metabolismo , Neurotransmissores/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septais/metabolismo , Tiazóis/farmacologia , Adaptação Fisiológica/efeitos dos fármacos , Regulação Alostérica , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico , Cadeia Alimentar , Córtex Insular/efeitos dos fármacos , Masculino , Odorantes , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacosRESUMO
Nonselective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson's disease and dystonia. Despite their efficacy in these and other central nervous system disorders, antimuscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the antiparkinsonian and antidystonic efficacy observed with the use of nonselective antimuscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of nonselective antimuscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here, we utilize genetic mAChR knockout animals in combination with nonselective mAChR antagonists to confirm that the M4 receptor activation is required for the locomotor-stimulating and antiparkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have antiparkinsonian and antidystonic efficacy in pharmacological and genetic models of movement disorders.
RESUMO
Herein, we report the SAR leading to the discovery of VU6028418, a potent M4 mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.
RESUMO
Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.
Assuntos
Regulação Alostérica/fisiologia , Córtex Cerebral/fisiologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tálamo/fisiologia , Adaptação Psicológica/efeitos dos fármacos , Anedonia/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Optogenética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células Piramidais/fisiologia , Tálamo/metabolismoRESUMO
Stress can precipitate or worsen symptoms of many psychiatric illnesses. Dysregulation of the prefrontal cortex (PFC) glutamate system may underlie these disruptions and restoring PFC glutamate signaling has emerged as a promising avenue for the treatment of stress disorders. Recently, we demonstrated that activation of metabotropic glutamate receptor subtype 3 (mGlu3) induces a postsynaptic form of long-term depression (LTD) that is dependent on the activity of another subtype, mGlu5. Stress exposure disrupted this plasticity, but the underlying signaling mechanisms and involvement in higher-order cognition have not yet been investigated. Acute stress was applied by 20-min restraint and early reversal learning was evaluated in an operant-based food-seeking task. We employed whole-cell patch-clamp recordings of layer 5 prelimbic (PL)-PFC pyramidal cells to examine mGlu3-LTD and several mechanistically distinct mGlu5-dependent functions. Acute stress impaired both mGlu3-LTD and early reversal learning. Interestingly, potentiating mGlu5 signaling with the mGlu5 positive allosteric modulator (PAM) VU0409551 rescued stress-induced deficits in both mGlu3-LTD and reversal learning. Other aspects of PL-PFC mGlu5 function were not disrupted following stress; however, signaling downstream of mGlu5-Homer interactions, phosphoinositide-3-kinase (PI3K), Akt, and glycogen synthase kinase 3ß was implicated in these phenomena. These findings demonstrate that acute stress disrupts early reversal learning and PL-PFC-dependent synaptic plasticity and that potentiating mGlu5 function can restore these impairments. These findings provide a framework through which modulating coordinated mGlu3/mGlu5 signaling may confer benefits for the treatment of stress-related psychiatric disorders.