data + articles · 8 listed
newest 2023spec sheet8 rows
LY2033298 is a preclinical positive allosteric modulator of the M4 muscarinic acetylcholine receptor; it was the first small molecule selective enough to test whether activating M4 on its own could produce an antipsychotic effect.
- antipsychotic-like activity in rodent models without D2 blockade
- subtype selectivity achieved through an allosteric site
- amplifies acetylcholine that is already there rather than flooding the receptor
- human tolerability never studied
- binds M2 as well as M4
- much weaker cooperativity at rodent receptors than human ones
- no established route to a human dose
Overview
Historically important out of all proportion to what it can actually do. A blunt instrument by current standards, with a stubborn rodent-to-human gap and a documented habit of spilling onto M2, but this is the compound that turned the M4 antipsychotic idea from a hypothesis into something testable.
- The selectivity of LY2033298 does not come from binding only M4. It binds M2 as well, and at M2 the very same molecule behaves as a positive or a strongly negative modulator depending on which agonist happens to be in the assay.
Mechanism
LY2033298 binds an site on the M4 receptor rather than the pocket, and it raises both the affinity and the efficacy of acetylcholine there while leaving binding essentially unchanged [1][2]. Because the pocket is less conserved across M1 to M5 than the orthosteric one, its selectivity comes from strong positive cooperativity with specifically at M4, not from a failure to bind the other subtypes; the same molecule does bind M2, where its effect flips between positive and strongly negative depending on which is present [3].
In rat striatal slices it reduced evoked release, and in vivo it potentiated an orthosteric 's suppression of conditioned avoidance responding, an effect lost in M4 knockout mice [2]. The reason this matters for psychosis is a property of the receptor rather than of this : M4 receptors on striatal spiny projection neurons, when activated, produce a sustained fall in striatal release with no action at at all [5]. Its cooperativity with is markedly weaker at the mouse receptor than at the human one, so most rodent work with it required an orthosteric alongside [4].
receptor fingerprint
M4 (CHRM4)Positive allosteric modulator
M2 (CHRM2)Allosteric modulator, probe dependent
Safetyrisks and cautions, not medical advice
No human safety data for LY2033298 has been published and no trial of it appears in the ClinicalTrials.gov registry, so everything known about its tolerability comes from rodents. The predictable hazard for anything that raises muscarinic tone is the peripheral cholinergic load, the problem that limited xanomeline until it was paired with a peripherally restricted blocker; an M4-selective modulator should in principle avoid the M2 and M3 part of that, but the M2 activity documented for this molecule means the assumption is not safe to make [3]. In hamsters, 10 to 40 mg/kg had no effect on light-induced circadian phase shifts given alone, and shifted them only when combined with an orthosteric agonist [6]. Whether it affects human heart rate, salivation or gut motility is not known, because nobody has looked.
History
LY2033298 came out of Eli Lilly's neuroscience group and was described in 2008 as the first small molecule selective enough to put the M4 hypothesis of antipsychotic action to a direct test. Almost all of the pharmacology that followed was done with Arthur Christopoulos's laboratory at Monash, which spent the next decade using it as the reference allosteric ligand for M4 and, in the process, using it to define what probe dependence and species variability mean for allosteric drugs generally. Lilly went on to radiolabel a close analogue, LY2119620, as a probe for the human M2 and M4 allosteric sites. There is no published record of LY2033298 itself entering clinical trials.
Reputation
Among muscarinic pharmacologists LY2033298 is regarded as a landmark rather than a drug; it is the compound most often cited as proof that subtype selectivity at muscarinic receptors could be bought with allostery when it could not be bought with orthosteric chemistry. Its standing is complicated by two findings from its own literature, that the size of its effect depends on which agonist is present and that human and rodent receptors do not respond alike, both now treated as general cautions about allosteric modulators rather than as flaws unique to it. Outside that specialty it is unknown.
Subjective profileweighing the evidence above
Historically important out of all proportion to what it can actually do. A blunt instrument by current standards, with a stubborn rodent-to-human gap and a documented habit of spilling onto M2, but this is the compound that turned the M4 antipsychotic idea from a hypothesis into something testable.
Resources
This entry is here for reference.
Research
- 2008first citedAllosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia
- 2023most recentPharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structu…
- 1.Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia
- 2.Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties
- 3.Probe dependence in the allosteric modulation of a G protein-coupled receptor: implications for detection and validation of allosteric ligand effects
- 4.Impact of species variability and 'probe-dependence' on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor
- 5.Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release
- 6.LY2033298, a positive allosteric modulator at muscarinic M₄ receptors, enhances inhibition by oxotremorine of light-induced phase shifts in hamster circadian activity rhythms.
- 7.Development of a radioligand, [3H]LY2119620, to probe the human M2 and M4 muscarinic receptor allosteric binding sites
- 8.Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics
8 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is LY2033298 something I can take?
No. It is a laboratory reagent with no recorded human exposure, no registered trial and no approved use anywhere.
Does it work the same way as Cobenfy?
Only in the broad sense that both raise muscarinic signalling to treat psychosis. Cobenfy is xanomeline, a direct agonist at M1 and M4, combined with trospium to blunt the peripheral effects; the FDA approved it for schizophrenia in adults on 26 September 2024. LY2033298 mostly works by making the M4 receptor more responsive to the acetylcholine already present, though it does show some direct activation of its own.
Why did anyone start looking at M4 for psychosis?
Because activating M4 receptors on striatal spiny projection neurons produces a lasting drop in striatal dopamine release, which is the endpoint D2 blockers reach by a cruder route. Reaching it without occupying D2 is what makes the approach interesting. That chain is well established in rodents; the human evidence so far comes from xanomeline-based drugs rather than from selective M4 modulators, and the one selective M4 modulator that reached a phase 2 efficacy readout, emraclidine, did not beat placebo.
Adverse effects
- human tolerability never studied
- binds M2 as well as M4
- much weaker cooperativity at rodent receptors than human ones
- no established route to a human dose