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VU0467154 is a preclinical positive allosteric modulator of the M4 muscarinic receptor, built at Vanderbilt as an in vivo tool compound, and it is the molecule most of the rodent evidence for the M4 antipsychotic hypothesis actually rests on.
- reverses NMDA antagonist-induced hyperlocomotion and learning deficits in rodents
- no measurable activity at M1, M2, M3 or M5
- reduces alcohol self-administration and cue-induced relapse in rats
- orally active in animals, which earlier M4 PAMs were not
- roughly 35 fold weaker at the human receptor than the rat one
- narrow effective dose range in mice, with benefit lost at higher doses
- off-target inhibition of the adenosine transporter
- reduced breath rate on chronic dosing in mice
- no human data of any kind
Overview
The workhorse of the field rather than a drug candidate. Potent and clean at the rat receptor and roughly thirty-five times weaker at the human one, which is exactly the wrong direction for a compound whose entire job is to predict what will happen in people.
- The dopamine suppression that M4 activation produces does not stop when the drug leaves; striatal dopamine release stays depressed for more than thirty minutes afterwards, and the whole effect disappears if CB2 cannabinoid receptors are blocked.
Mechanism
VU0467154 binds the M4 site and potentiates there rather than activating the receptor in acetylcholine's place. In a calcium mobilisation assay it gave an EC50 near 18 nM at the rat receptor and near 630 nM at the human receptor, with no measurable activity at M1, M2, M3 or M5 up to 30 uM in either species [2]. Raising M4 signalling on striatal spiny projection neurons depresses striatal release for more than half an hour after the drug is washed out, and both that depression and the antipsychotic-like behaviour of M4 activators require intact CB2 cannabinoid receptor signalling, which was not something anyone expected [3].
In rodents it reversed MK-801-induced hyperlocomotion and the associative learning deficits that accompany it, including in a touchscreen visual discrimination task, and those reversals were absent in M4 knockout mice, which is the control that ties the behaviour to the receptor rather than to the chemical series [1]. It also cut alcohol self-administration and cue-induced reinstatement in rats, and microinjection into the dorsolateral striatum alone reproduced the systemic effect [4].
receptor fingerprint
M4 (CHRM4), ratPositive allosteric modulator
M4 (CHRM4), humanPositive allosteric modulator
M1, M2, M3 and M5No measurable activity
(nucleoside) transporterInhibitor
Safetyrisks and cautions, not medical advice
There is no recorded human exposure to VU0467154 and no registered clinical trial, so nothing can be said about its safety in people. In mice the useful range proved narrow: benefit on anxiety, social, cognitive and respiratory measures appeared at 3 mg/kg but not at 1 or 10 mg/kg, sociability fell in treated wild-type animals, and breath rate dropped moderately across a 44 day course [5]. ChEMBL also carries an off-target measurement from the discovery paper, inhibition of the human adenosine transporter with an IC50 near 240 nM, close enough to the active range that it belongs in any reading of the in vivo results [2]. The peripheral muscarinic hazards that matter for cholinergic drugs, salivation, gut motility and heart rate, have not been characterised for this compound in any species at therapeutic exposures.
History
VU0467154 was made at the Vanderbilt Center for Neuroscience Drug Discovery in a programme run with AstraZeneca, and was published in 2014 as the successor to the earlier Vanderbilt M4 PAM VU0152100, with better potency and pharmacokinetics so it could be dosed orally in behaving animals. The 2016 optimisation paper that describes how it was found is unusually candid about the difficulty of the chemistry: steep structure-activity relationships, large species differences in modulator pharmacology, and small structural changes that quietly destroyed brain penetration. It has stayed a tool compound and no clinical development of it has been reported. The selective M4 modulator that did reach patients was emraclidine, developed by Cerevel and acquired by AbbVie, and in November 2024 both of its phase 2 EMPOWER trials reported failing to separate from placebo on total PANSS score at week 6.
Reputation
Within muscarinic pharmacology VU0467154 is the reference in vivo M4 PAM. A large share of the rodent literature that built the M4 antipsychotic case, plus the extensions into Rett syndrome models, Huntington models and alcohol use disorder, is built on this single molecule. That concentration is also the fair criticism of the field, since a body of evidence resting on one tool compound with a thirty-five-fold species gap is thinner than the volume of papers makes it look. Outside the laboratory it has no reputation at all.
Subjective profileweighing the evidence above
The workhorse of the field rather than a drug candidate. Potent and clean at the rat receptor and roughly thirty-five times weaker at the human one, which is exactly the wrong direction for a compound whose entire job is to predict what will happen in people.
Resources
This entry is here for reference.
Research
- 2014first citedSelective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behaviora…
- 2023most recentPharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structu…
- 1.Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents
- 2.Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs
- 3.Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release
- 4.Acetylcholine Muscarinic M4 Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents
- 5.Optimized Administration of the M4 PAM VU0467154 Demonstrates Broad Efficacy, but Limited Effective Concentrations in Mecp2+/- Mice
- 6.Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics
6 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Can I buy VU0467154?
It is sold to laboratories as a research chemical, which is not the same as being available as a drug. There is no human dose, no registered trial and no safety data in people.
If it works so well in rats, why has it not gone into humans?
Partly because it is a tool compound rather than a development candidate, and partly because it is about thirty-five times less potent at the human M4 receptor than at the rat one. A compound with that gap would need a much higher human exposure to do the same thing, which changes the safety calculation entirely.
Does an M4 PAM block dopamine the way an antipsychotic does?
No, and that is the point of the approach. It does not bind dopamine receptors at all. It boosts acetylcholine signalling at M4 receptors on striatal neurons, and those neurons then reduce how much dopamine gets released. The endpoint overlaps with what a D2 blocker achieves; the route there does not, which is why the side effect profile was expected to differ.
Adverse effects
- roughly 35 fold weaker at the human receptor than the rat one
- narrow effective dose range in mice, with benefit lost at higher doses
- off-target inhibition of the adenosine transporter
- reduced breath rate on chronic dosing in mice
- no human data of any kind