Delving into the Latest Updates on VU0357017 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

VU0357017

Target

M1 receptor

Action

agonists

Mechanism

M1 receptor agonists(Muscarinic acetylcholine receptor M1 agonists)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Alzheimer DiseaseSchizophrenia

Originator Organization

Vanderbilt University

Active Organization-

Inactive Organization

Vanderbilt University

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC18H27N3O3

InChIKeyZBSSIYGXZQZYDM-UHFFFAOYSA-N

CAS Registry1135681-23-0

Schizophrenia is a mental disorder with multifactorial etiology including positive, negative and cognitive symptoms. Nitric oxide (NO֗)-related biochemical pathways significantly contribute to the disease's pathophysiology and subsequent antipsychotic treatment. Recently, metabotropic glutamatergic (mGlu) or muscarinic (M) receptors have been considered as potent antipsychotics with the potential to reverse cognitive symptoms. The aim of this study was to investigate how selected mGlu or muscarinic receptor ligands regulate the most important aspects of NO֗-related neurotransmission.

METHODS:

In this study, MK-801-the tool compound that induces schizophrenia-related changes-was used alone or with mGlu or muscarinic receptor ligands. Positive allosteric modulators (PAM) of mGlu₂ (LY487379), mGlu₅ (CDPPB), M₁ (VU0357017) and M₄ (VU0152100) receptors were administered. cGMP levels, superoxide dismutase (SOD) activity, nitrite and GLT-1 s-nitrosilation processes were investigated in mouse brain and plasma samples, while oxidative stress was measured in vitro with the use of mouse or human astrocytic cell lines.

RESULTS:

MK-801 did not change cGMP levels, while a decrease was observed in mice treated with VU0357017 or LY487379 in parallel. Increased SOD activity was observed in the cortex of MK-801-treated mice, and the compounds, with the exception of CDPPB, prevented this effect. The investigated compounds also prevented an MK-801-induced increase in plasma nitrite levels. GLT-1 protein was decreased after MK-801 treatment which was not evident in mice administered with muscarinic or mGlu ligands. GLT-1 S-nitrosilation was increased in all groups. In vitro studies revealed the potency of these compounds in counteracting MK-801-induced oxidative stress.

CONCLUSIONS:

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.

01 May 2024·Pharmacology, biochemistry, and behavior

Prevention of MK-801-induced amnestic effect with combined activation of 5-HT1A and muscarinic receptors in mice

Article

Author: Rafało-Ulińska, Anna ; Cieślik, Paulina ; Wierońska, Joanna M

BACKGROUND:

Muscarinic or 5-HT_1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits.

METHODS:

Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT_1A receptor agonist (F15599) alone or in combinations with VU0357017 (M₁ receptor allosteric agonist), VU0152100 (M₄ receptor positive allosteric modulator), and VU0238429 (M₅ receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT_1A receptors and the level of GAD₆₅ in the frontal cortices (FCs) and hippocampi of the animals.

RESULTS:

F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT_1A expression in the hippocampi and decreased GAD₆₅ levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice.

CONCLUSION:

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 receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT_1A and GAD₆₅ dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.

01 Dec 2022·Biological psychiatry

Astrocytes Mediate Cholinergic Regulation of Adult Hippocampal Neurogenesis and Memory Through M1 Muscarinic Receptor

Article

Author: Gao, Tian-Ming ; Yang, Jian-Ming ; Hu, Neng-Yuan ; Li, Wei-Peng ; Li, Xiao-Wen ; Hu, Jian ; Su, Xiao-Hong

BACKGROUND:

In the neurogenic niches of the adult hippocampus, new functional neurons are continuously generated throughout life, and generation of these neurons has been implicated in learning and memory. Astrocytes, as components of the neurogenic niches, are critical in the regulation of adult hippocampal neurogenesis (AHN). However, little is known about how astrocytes receive and respond to extrinsic cues to regulate AHN.

METHODS:

By using a transgenic strategy to conditionally delete astrocytic CRHM1 in mice and AAV (adeno-associated virus)-mediated overexpression of astrocytic CHRM1 specifically in the hippocampal dentate gyrus, we systematically investigated the role of astrocytic CHRM1 in the regulation of AHN and the underlying mechanisms using the combined approaches of immunohistochemistry, retrovirus labeling, electrophysiology, primary astrocyte cultures, immunoblotting, and behavioral assays.

RESULTS:

We report that genetic ablation of CHRM1 in astrocytes led to defects in neural stem cell survival, neuronal differentiation, and maturation and integration of newborn neurons in the dentate gyrus. Astrocytic CHRM1-mediated modulation of AHN was mediated by BDNF (brain-derived neurotrophic factor) signaling. Furthermore, CHRM1 ablation in astrocytes impaired contextual fear memory. These impairments in both AHN and memory were rescued by overexpression of astrocytic CHRM1 in the dentate gyrus.

CONCLUSIONS:

Our findings reveal a critical role for astrocytes in mediating cholinergic regulation of AHN and memory through CHRM1.

100 Deals associated with VU0357017

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