Novel Selective Allosteric Activator of the M<sub>1</sub>Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats

Jones, Carrie K.; Brady, Ashley E.; Davis, Albert A.; Xiang, Zixiu; Bubser, Michael; Tantawy, Mohammed Noor; Kane, Alexander S.; Bridges, Thomas M.; Kennedy, J. Phillip; Bradley, Stefania Risso; Peterson, Todd E.; Ansari, M. Sib; Baldwin, Ronald M.; Kessler, Robert; Deutch, Ariel Y.; Lah, James J.; Levey, Aĺlan I.; Lindsley, Craig W.; Conn, P. Jeffrey

doi:10.1523/jneurosci.1850-08.2008

Cited by 223 publications

(243 citation statements)

References 44 publications

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“…Locomotor activity was assessed in open field chambers as previously described (see Jones et al, 2008). Briefly, rats were habituated to the chambers for 30 min, then pre-treated with either vehicle or VU0152100 (3-56.6 mg/kg, interperitoneal (i.p.)).…”

Section: Amphetamine-induced Hyperlocomotionmentioning

confidence: 99%

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Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Byun

Grannan

Bubser

et al. 2014

Neuropsychopharmacol

105

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Accumulating evidence suggests that selective M 4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M 4 activators were unsuccessful because of the lack of M 4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M 4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M 4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M 4 -mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M 4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M 4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

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Section: Amphetamine-induced Hyperlocomotionmentioning

confidence: 99%

“…), or oxotremorine sesquifumarate (1 mg/kg, s.c.) on autonomic and somatosensory system function were assessed at 5, 15, 60, 120, and 240-min post-injection using the Modified Irwin Neurological Test Battery (Irwin, 1968), as previously described (see Jones et al, 2008).…”

Section: Modified Irwin Test Batterymentioning

confidence: 99%

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Byun

Grannan

Bubser

et al. 2014

Neuropsychopharmacol

105

View full text Add to dashboard Cite

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“…Open-field activity was tested using SmartFrame open-field chambers (Kinder Scientific, San Diego, CA) as described previously (Jones et al, 2008;Byun et al, 2014). To examine potential sedative effects of compounds, rats were injected with vehicle, M-5MPEP, or Br-5MPEPy (18-56.6 mg/kg), or MTEP (5 mg/kg) and 30 min later placed in the test chambers for 60 min.…”

Section: Spontaneous Locomotor Activity and Pcp-induced Hyperlocomotionmentioning

confidence: 99%

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Gould

Amato

Bubser

et al. 2015

Neuropsychopharmacol

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Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5 ) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.

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“…TBPB displayed agonistic behavior and potentiates NMDA receptor currents at rat hippocampal M 1 mAChRs in vitro and was also shown to promote nonamyloidogenic APP processing in PC12 cells as measured by a decrease in Aβ42 levels and an increase in α-secretase metabolites. 129 Furthermore, TBPB elicited antipsychotic-like behavior in rodent models of schizophrenia.…”

Section: ■ M 1 Machr-selective Ligandsmentioning

confidence: 99%

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Davie

Christopoulos

Scammells

2013

ACS Chem. Neurosci.

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Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M 1 muscarinic acetylcholine receptor (M 1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M 1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M 1 mAChR, comprehensively summarize and critically evaluate the M 1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. KEYWORDS: M 1 mAChR, allosteric ligands, Alzheimer's disease, schizophrenia, cognitive deficits, memory T he muscarinic acetylcholine receptor (mAChR) family is a group of rhodopsin-like (Family A) G protein-coupled receptors (GPCRs) consisting of five distinct subtypes M 1 −M 5 . Activation of the M 1 , M 3 , and M 5 receptor subtypes primarily results in coupling to the G q/11 family of G proteins, activation of phospholipase C (PLC), release of inositol-1,4,5-trisphosphate (IP 3 ), and subsequent mobilization of intracellular calcium Ca 2+ . Activation of the M 2 and M 4 receptor subtypes primarily results in coupling to the G i/o family of G proteins, inhibition of adenylate cyclase (AC), reduction in cyclic AMP (cAMP), and a decrease in neurotransmitter release via the blockage of voltage-gated calcium channels (Figure 1). These pathways represent a generalized view of each receptor's coupling capacity, as all five subtypes couple to a broader range of G protein-and non-G protein-mediated signaling and regulatory pathways, 1 ultimately leading to the regulation of enzymes and neurotransmitters critical for intercellular chemical communication and biological function. In a ...

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Novel Selective Allosteric Activator of the M₁Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats

Cited by 223 publications

References 44 publications

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

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Novel Selective Allosteric Activator of the M1Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats

Cited by 223 publications

References 44 publications

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Contact Info

Product

Resources

About

Novel Selective Allosteric Activator of the M₁Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits