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VU319 is a Vanderbilt-discovered M1-selective positive allosteric modulator with minimal intrinsic agonist activity that completed a first-in-human single ascending dose trial without the cholinergic adverse effects that ended earlier compounds in the class.
- no dose-limiting cholinergic effects from 60 mg to 600 mg in healthy adults
- pharmacokinetics consistent with once daily dosing
- signals of central target engagement on event-related potentials at the higher doses
- clean four week GLP toxicology in rats and dogs
- treatment-emergent adverse events were more frequent on drug than on placebo, though none were dose limiting
- absorption increases with food, so exposure moves with meals
- repeat-dose tolerability in humans has not been reported
Overview
The most interesting compound in the M1 PAM class precisely because it was uneventful in humans; low agonism, no dose-limiting cholinergic effects up to 600 mg, and a half-life that supports once daily dosing. Whether any of that converts into cognitive benefit in patients is still entirely open.
- The intended backup to VU319 failed before VU319 did. VU6007496 was dropped in late-stage profiling after species-specific metabolism produced active or toxic metabolites that surfaced in a phenotypic seizure liability screen, leaving it usable as a tool compound in rats and nonhuman primates but not in mice.
Mechanism
VU319 potentiates at the M1 receptor with an EC50 near 492 nM, lifting the acetylcholine response to about 71% of maximum, while its own direct activity at M1 sits above 30 uM; that gap between modulation and activation is the point of the molecule [1]. It is penetrant, with a brain to plasma partition coefficient above 0.67 and an unbound brain to unbound plasma ratio above 0.9, and showed no appreciable off-target activity in an ancillary pharmacology panel [1].
Because it modulates rather than activates, its effect should scale with that is already being released rather than switching M1 on independently, which is the property the field has been chasing since intrinsic agonism was tied to seizure liability [4][5]. In the phase 1 study, exploratory cognitive tasks and event-related potentials showed drug-related central activity at the higher doses, which is target engagement rather than clinical benefit [2].
receptor fingerprint
M1 (CHRM1)Positive allosteric modulator
Safetyrisks and cautions, not medical advice
In rats, dogs and nonhuman primates VU319 produced no cholinergic adverse effects, and four week GLP toxicology in rats and dogs was likewise free of them [1]. In the first-in-human single ascending dose study, 52 healthy adults aged 18 to 55 received 60, 120, 240, 400 or 600 mg orally, six on drug and two on placebo per cohort, plus a food effect arm; no dose-limiting side effects appeared anywhere across that range, with 33 treatment-emergent adverse events across the five active cohorts against 14 on placebo [2].
That is the opposite result to MK-7622 and PF-06827443, and the authors attribute the difference to the absence of allosteric agonism rather than to selectivity, since all three compounds are M1-selective [1][5]. What this does not establish is chronic safety or safety in patients; a registered multiple ascending dose study was withdrawn before enrolling anyone, so repeated dosing in humans has not been reported, and neither has exposure in people with cognitive impairment.
History
VU319 came out of the Warren Center for Neuroscience Drug Discovery at Vanderbilt, from the Conn and Lindsley groups, and was carried through IND-enabling work on academic funding, an unusual route for a CNS clinical candidate [1]. Vanderbilt itself sponsored the first-in-human phase 1 trial (NCT03220295), which ran from July 2017 to October 2019 and enrolled 52 healthy volunteers across a single ascending dose arm and a food effect arm [2]. In May 2020, Acadia Pharmaceuticals and Vanderbilt announced an exclusive worldwide license covering the M1 program, including the lead compound then in phase 1; Vanderbilt's registered multiple ascending dose study was subsequently withdrawn, the stated reason being that further development had been outlicensed to Acadia. Later Vanderbilt papers refer to the molecule as VU319/ACP-319 [3].
Reputation
Within the muscarinic field VU319 is treated as the demonstration that a genuinely low-agonism M1 PAM can be given to humans without the cholinergic toxicity that stopped the Merck and Pfizer efforts, and it is discussed in exactly those terms [1][5]. It is otherwise unknown; there is no consumer presence, no supply, and no efficacy data in any patient population. The published enthusiasm is about the safety result, not about cognition.
Subjective profileweighing the evidence above
The most interesting compound in the M1 PAM class precisely because it was uneventful in humans; low agonism, no dose-limiting cholinergic effects up to 600 mg, and a half-life that supports once daily dosing. Whether any of that converts into cognitive benefit in patients is still entirely open.
Resources
This entry is here for reference.
Research
- 2018first citedM1-positive allosteric modulators lacking agonist activity provide the optimal profile for enha…
- 2025most recentDiscovery of VU0467319: an M1 Positive Allosteric Modulator Candidate That Advanced into Clinic…
- 1.Discovery of VU0467319: an M1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials
- 2.Safety, tolerability, pharmacokinetic and pharmacodynamic effects of the muscarinic M1 positive allosteric modulator VU0467319 for Alzheimer's disease: a single ascending-dose study in healthy participants
- 3.Discovery of VU6007496: Challenges in the Development of an M1 Positive Allosteric Modulator Backup Candidate
- 4.M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition
- 5.Opportunities and challenges for the development of M1 muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits
5 listed here; entry last updated July 2026
Reviews
My notesprivate to this device
FAQ
Is VU319 available to buy?
No. It is an investigational compound that has completed one phase 1 trial and is licensed to Acadia Pharmaceuticals. There is no legitimate supply.
Does VU319 actually improve cognition?
Not established. The phase 1 study saw drug-related changes on exploratory cognitive tasks and event-related potentials at higher doses in healthy volunteers, which shows the drug is doing something centrally. No trial in people with cognitive impairment has been reported.
Why was VU319 tolerated when MK-7622 was not?
Because it barely activates M1 on its own. Direct agonist potency sits above 30 uM while it potentiates acetylcholine in the high nanomolar range, so it amplifies a signal that is already there instead of generating one. Intrinsic agonism, not M1 selectivity, is what separates the tolerated compounds from the ones that caused convulsions in animals.
Can I take it with donepezil?
There is no human data on that combination. The pharmacological logic is that a modulator needs acetylcholine to act on, so a cholinesterase inhibitor would in principle supply more of it. That exact combination has only been tested with MK-7622, where it produced no cognitive benefit and more cholinergic side effects than placebo.
Adverse effects
- treatment-emergent adverse events were more frequent on drug than on placebo, though none were dose limiting
- absorption increases with food, so exposure moves with meals
- repeat-dose tolerability in humans has not been reported