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Oxotremorine is a non-selective muscarinic agonist used in the laboratory to produce a reproducible cholinergic syndrome in rodents: tremor, hypothermia, salivation and analgesia.
- Reproducible, atropine-reversible cholinergic syndrome in rodents
- Standard positive control for central muscarinic activation
- Active across M1 to M5, so it does not bias an assay toward one subtype
- Tremor
- Hypothermia
- Profuse salivation and lacrimation
- Diarrhoea
- Bradycardia
Overview
A pure tool compound, and a very good one. Its value is that the response it produces is large, fast and reversed by atropine, which makes it the default positive control when a new muscarinic drug has to be shown either to mimic central cholinergic activation or to block it. It is not a candidate for anything and was never meant to be.
- Oxotremorine was discovered as the active metabolite of something else; tremorine, the compound it displaced, turned out to be inert until the body converted it.
- The tremor it produces vanishes entirely in M2 knockout mice, which is how the field established that the classic central muscarinic tremor is an M2 effect and not an M1 one.
Mechanism
Oxotremorine is an orthosteric with no meaningful subtype selectivity. Across cloned human receptors in a single receptor selection and amplification panel its EC50 values were 390 nM at M1, 19 nM at M2, 210 nM at M3, 33 nM at M4 and 55 nM at M5, a spread of about twentyfold with the tightest values at the Gi-coupled subtypes. Its efficacy is intermediate rather than full; at transfected M1 receptors it ranks below , carbachol and oxotremorine-M, and the quaternary trimethylammonium group that oxotremorine-M carries and oxotremorine lacks appears to be what buys full agonist activity [2].
The in vivo syndrome is subtype resolved. In M2 knockout mice the tremor, hypothermia and analgesia produced by oxotremorine are absent, while M4 knockouts retain them, so the classic tremorgenic and hypothermic effects run through M2 rather than through M1 [3][6]. Salivation is not carried by M2, and M4 contributes only modestly to it [6]. In rat striatum the presynaptic autoreceptor it acts through behaves as M4, and unlike its quaternary analogue its effect there is not enhanced by the modulator brucine [5].
receptor fingerprint
M1 (CHRM1)Agonist, submaximal efficacy
M2 (CHRM2)Agonist
M3 (CHRM3)Agonist
M4 (CHRM4)Agonist
M5 (CHRM5)Agonist
Safetyrisks and cautions, not medical advice
Oxotremorine is a preclinical reagent with no therapeutic use and no established human exposure; what is known about its toxicity comes from rodents, where the intended effect and the toxicity are the same thing. Doses that produce tremor also produce hypothermia, profuse salivation, lacrimation, diarrhoea and bradycardia, all of it muscarinic and all of it reversible by atropine [6]. Because tremor and hypothermia run through M2, an agent that spares M2 will not reproduce them, which is precisely how the assay earns its keep. Nicotinic tone sets the gain: mice lacking the alpha5 nicotinic subunit show significantly larger salivation and tremor responses to the same dose, implicating autonomic ganglionic transmission in the size of the response [5]. Human safety data do not exist. Nobody has run the study, which is not the same thing as the compound being safe.
History
Oxotremorine came out of work on tremorine, a butyne diamine reported in the late 1950s to produce a parkinsonian tremor in animals. Cho, Haslett and Jenden showed in the early 1960s that tremorine is a prodrug and that oxotremorine is the metabolite doing the work, and the parent compound was retired in its favour. It has stayed in continuous use as a tool ever since. Its quaternary analogue oxotremorine-M, in tritiated form, remains one of the standard radioligands for labelling the high-affinity agonist state of muscarinic receptors, which is why so many published Ki values for muscarinic agonists are quoted against it.
Reputation
Regarded purely as bench apparatus. In the muscarinic literature oxotremorine-induced tremor is the name of an assay rather than a description of a drug effect, and a compound's ability to block it is a routine way of claiming central antimuscarinic activity. It has no reputation outside the laboratory and no user community, which is the correct outcome for a compound whose signature action is making animals shake.
Subjective profileweighing the evidence above
A pure tool compound, and a very good one. Its value is that the response it produces is large, fast and reversed by atropine, which makes it the default positive control when a new muscarinic drug has to be shown either to mimic central cholinergic activation or to block it. It is not a candidate for anything and was never meant to be.
Resources
This entry is here for reference.
Research
- 1962first citedThe peripheral actions of oxotremorine, a metabolite of tremorine.
- 2004most recentNicotinic acetylcholine receptor alpha5 subunits modulate oxotremorine-induced salivation and t…
- 1.The peripheral actions of oxotremorine, a metabolite of tremorine.
- 2.Generation and pharmacological analysis of M2 and M4 muscarinic receptor knockout mice.
- 3.Investigations into the physiological role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice.
- 4.Pharmacologic comparison of selected agonists for the M1 muscarinic receptor in transfected murine fibroblast cells (B82).
- 5.Nicotinic acetylcholine receptor alpha5 subunits modulate oxotremorine-induced salivation and tremor.
- 6.The effects of brucine and alcuronium on the inhibition of [3H]acetylcholine release from rat striatum by muscarinic receptor agonists.
- 7.The relationship between agonist intrinsic activity and the rate of endocytosis of muscarinic receptors in a human neuroblastoma cell line.
7 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
What is the difference between oxotremorine and oxotremorine-M?
Oxotremorine-M carries a quaternary trimethylammonium group where oxotremorine has a tertiary pyrrolidine. That makes oxotremorine-M a full agonist where oxotremorine is only partial, and, as with quaternary compounds generally, its permanent positive charge keeps it from crossing the blood-brain barrier readily. The tritiated form of oxotremorine-M is the workhorse radioligand for the high-affinity agonist state of muscarinic receptors.
Can I take oxotremorine?
No. There is no human formulation, no established human dose and no therapeutic indication. It exists to make laboratory animals tremble on cue.
Why is it used to test antimuscarinic drugs?
Because the response is large, quick and specific. If a candidate blocks oxotremorine-induced tremor and hypothermia in mice, it has demonstrably reached central muscarinic receptors. Run the other way, whether a candidate produces the syndrome itself, the same assay screens for cholinergic side effect liability.
If it causes tremor, does that mean muscarinic agonists cause Parkinson's disease?
No. The tremor is a pharmacological effect of acute M2 activation and it stops when the drug clears or when atropine is given. Parkinson's disease is a degenerative loss of dopaminergic neurons. The assay was historically used as a rough tremor model, not as a disease model.
Adverse effects
- Tremor
- Hypothermia
- Profuse salivation and lacrimation
- Diarrhoea
- Bradycardia