VU0152100 / Vanderbilt University Medical Center - LARVOL DELTA

Receptor subtype specific modulation of muscarinic pathways: a mechanistically distinct therapeutic strategy for schizophrenia (ECNP 2025) - "VU0152100, a selective M4 PAM, exhibits antipsychotic-like effects in rodent models, reducing amphetamine induced locomotor hyperactivity and reversing behavioral deficits...NBI-1117568, a selective M4 orthosteric agonist in Phase 2 trials for schizophrenia, attenuates dopaminergic hyperactivity and restores sensorimotor gating without sedative or motor impairments. Blarcamesine has shown neuroprotective and cognitive enhancing effects in multiple models... Targeting mAChRs, particularly M1 and M4, provides a receptor subtype specific strategy to address unmet needs in schizophrenia. KarXT and emraclidine represent leading agents in clinical development. Emerging modulators such as BQCA, AC-42, and the VU series highlight the diversity of mechanisms and potential for precision treatment tailored to receptor expression profiles and schizophrenia endophenotypes [3]."

CNS Disorders • Psychiatry • Schizophrenia

Allosteric modulation of M1 or M4 muscarinic receptors restores eNOS expression and L-arginine metabolism in dementia models and synergizes with NO releasers. (PubMed, Pharmacol Biochem Behav) - "eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Psychiatry • Schizophrenia • NOS3 • PRMT5

The impact of muscarinic and mGlu receptors modulators on MK-801-induced impairments in NO-dependent processes both in vitro and in vivo. (PubMed, Pharmacol Rep) - "The present data confirm that both mGlu and muscarinic receptor ligands may exert antipsychotic effects through biochemical pathways regulated by NO֗, in particular by decreasing oxidative stress indicators."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry • Schizophrenia

Co-stimulation of muscarinic M1 and M4 acetylcholine receptors prevents later cocaine reinforcement in male and female mice, but not place-conditioning. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Mice were pre-treated with the M1 receptor partial agonist VU0364572, M4 receptor positive allosteric modulator VU0152100, or VU0364572 + VU0152100 two weeks prior to acquisition of cocaine intravenous self-administration (IVSA)...The cocaine IVSA findings confirm unusual long-lasting "anticocaine" effects of muscarinic M1 + M4 receptor stimulation. Thus, in mice, simultaneous stimulation of both receptor subtypes seems to produce potential neuroplastic changes that yield lasting effects."

Journal • Preclinical • CNS Disorders • Psychiatry

Prevention of MK-801-induced amnestic effect with combined activation of 5-HT1A and muscarinic receptors in mice. (PubMed, Pharmacol Biochem Behav) - "Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptor activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptor activators reverse MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

The muscarinic receptor subtype M4 improves decision making and reduces impulsivity in rats (Neuroscience 2023) - "Male and female Long Evans rats (n = 32) received xanomeline (M1/M4 agonist), VU0152100 (M4 positive allosteric modulator), or pirenzepine (peripherally-acting M1 antagonist) before task performance...Muscarinic subtype modulation, with a particular focus on M4, shows promise as a therapeutic approach for addressing cognitive symptoms in neuropsychiatric disorders. Further research is required to uncover the specific mechanisms and neuroanatomical areas that underlie these cognitive improvements."

Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Activation of Metabotropic Glutamate Receptor (mGlu) and Muscarinic Receptors (M, M, and M), Alone or in Combination, and Its Impact on the Acquisition and Retention of Learning in the Morris Water Maze, NMDA Expression and cGMP Synthesis. (PubMed, Biomolecules) - "Here, we show that muscarinic receptor activators (VU0357017, VU0152100, and VU0238429) and an mGlu receptor activator, LY487379, dose-dependently prevented the development of cognitive disorders as a result of MK-801 administration in the MWM. The investigated compounds at the highest doses reversed this MK-801-induced effect. Neither the procedure nor the treatment resulted in changes in GluN2B-NMDA expression."

Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Psychiatry • Schizophrenia • GRIN2B

Effects of acute and repeated administration of the selective M PAM VU0152099 on cocaine versus food choice in male rats. (PubMed, Addict Biol) - "To compare and contrast effects of M versus M stimulation, we tested whether the M PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signalling factor, required for M -mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M -mediated suppression of cocaine self-administration. These findings support the potential usefulness of M PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M -selective ligands, and show that M and M stimulation modulate cocaine-taking behaviour by distinct mechanisms."

Journal • Preclinical • CNS Disorders • Psychiatry • Substance Abuse • RASGRP1

Serotonergic-Muscarinic Interaction within the Prefrontal Cortex as a Novel Target to Reverse Schizophrenia-Related Cognitive Symptoms. (PubMed, Int J Mol Sci) - "Activators of 5-HT (F15599), M (VU0357017), M (VU0152100), or M (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction."

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

Striatal and nigral muscarinic type 1 and type 4 receptors modulate levodopa-induced dyskinesia and striato-nigral pathway activation in 6-hydroxydopamine hemilesioned rats. (PubMed, Neurobiol Dis) - "Reverse microdialysis allowed to deliver the mAChR antagonists telenzepine (M1 subtype preferring), PD-102807 and tropicamide (M4 subtype preferring), as well as the selective M4 mAChR positive allosteric modulator VU0152100 in striatum or substantia nigra, while levodopa was administered systemically. Conversely, striatal M4 mAChRs can both facilitate and inhibit dyskinesia, possibly depending on their localization. Potentiation of striatal and nigral M4 mAChR transmission leads to powerful multilevel inhibition of striato-nigral pathway and attenuation of dyskinesia."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

The allosteric modulation of group III mGlu receptors as target for antipsychotic or antidepressant drugs (WFSBP 2017) - "VU0152100 the muscarinic M4 receptor PAM (3) was also active in animal models of schizophrenia, dose-dependently reversing MK-801-induced disruptions in MK-801 and amphetamine –induced hyperactivity, DOI-induced head twitches, modified forced swim test, social interactions and novel object recognition tests.When mGlu4 and 5-HT1A receptor were co-expressed in the T-Rex 293 cells, the fluorescence resonance energy transfer (FRET) studies revealed the close vicinity of both receptors. The experiments with the use of proximity ligation assay (PLA) conducted on a primary cultures of astrocytes or neurons have shown a positive PLA signal, which indicated that both receptors are placed in a close vicinity, which enables the potential dimerization of bot receptors."

Preclinical • Biosimilar • Depression • Schizophrenia

The high efficacy of muscarinic M4 receptor in D1 medium spiny neurons reverses striatal hyperdopaminergia. (PubMed, Neuropharmacology) - "In vivo experiments with acetylcholinesterase inhibitors donepezil and tacrine, as well as with the positive allosteric modulators of M receptor VU0152100 and VU0010010 show that this effect is sufficient to reverse the increased locomotor activity of DAT-knockout mice. This suggests that M receptors could be a novel therapeutic target to treat hyperactivity disorders."

Clinical • Journal

Simultaneous activation of muscarinic and GABA receptors as a bidirectional target for novel antipsychotic. (PubMed, Behav Brain Res) - "...Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs...Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test...Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions. Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics. "

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