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McN-A-343 is a quaternary muscarinic agonist that served for decades as the standard tool for identifying M1-mediated responses, and which is now understood to owe that apparent selectivity to uneven efficacy and to a second, allosteric binding site rather than to selective binding.
- A usable probe for M1 and M4 mediated responses once efficacy is accounted for
- Peripherally restricted, so central effects do not confound the readout
- The reference bitopic orthosteric and allosteric ligand
- Bronchospasm in anaesthetised animals
- Pressor response and tachycardia
- Off-target 5-HT3 and 5-HT4 antagonism
- Local anaesthetic activity
Overview
A cautionary tale worth knowing before trusting any compound called selective. Thirty years of papers used it to assign responses to M1 receptors; the affinity measurements show it binding all five subtypes at roughly the same low micromolar strength, so the selectivity was never in the binding at all. The compound is still useful, but only when what it is actually doing gets stated correctly.
- Cutting McN-A-343 down to its 3-chlorophenylcarbamate fragment yields a pure allosteric modulator with no agonist activity of its own; the interesting half of the molecule was the part that never touched the acetylcholine site.
Mechanism
McN-A-343 binds all five subtypes with similar and unremarkable affinity. Against [3H]NMS at human receptors expressed in CHO cells its Ki values run about 1950 nM at M1, 3236 nM at M2, 2399 nM at M3, 9120 nM at M4 and 3802 nM at M5. Its apparent M1 selectivity comes from efficacy rather than affinity: it is a partial whose relative efficacy is highest at M1 and M4, which in a tissue with substantial receptor reserve reads as selectivity and in a tissue without one can read as antagonism [1]. In transfected fibroblasts it is among the least efficacious agonists tested and it inhibits carbachol-stimulated phosphoinositide hydrolysis outright [2]. The modern account adds a second site.
Truncating the molecule yields fragments built around 3-chlorophenylcarbamate that are pure modulators of the M2 receptor, positive toward the [3H]NMS and negative toward efficacy, and mutating Tyr177 in the second extracellular loop, a residue known to matter for classical allosteric modulators, blunts that effect. McN-A-343 is therefore a bitopic occupying the orthosteric pocket and an allosteric site simultaneously, with the allosteric half directing what the orthosteric half signals [7]. That site is not the one gallamine occupies, and comparable mutations in M2 and M4 suggest the compound uses different receptor regions in the two subtypes to reach ERK1/2 [1].
receptor fingerprint
M1 (CHRM1)Partial agonist, bitopic
M2 (CHRM2)Partial agonist plus allosteric modulator at a distinct site
M3 (CHRM3)Partial agonist, low efficacy
M4 (CHRM4)Partial agonist
M5 (CHRM5)Partial agonist, low efficacy
Safetyrisks and cautions, not medical advice
There is no human use and no human dosing data for McN-A-343, so its profile is an animal one. It is a quaternary ammonium compound and does not penetrate the blood-brain barrier after peripheral administration, which confines its effects to the periphery [1]. Given intravenously to anaesthetised guinea pigs it produces dose-dependent bronchospasm, an effect some other M1-preferring agonists escape because they reach the brain and trigger a compensating sympathetic discharge that this compound cannot [7].
Its signature systemic effect is a rise in blood pressure and heart rate through stimulation of sympathetic ganglia, atropine-sensitive and not blocked by hexamethonium [1]. It also carries documented non-muscarinic activity that complicates its use as a probe: activation of some nicotinic receptor types, antagonism at 5-HT3 and 5-HT4, inhibition of an uptake mechanism, and a local anaesthetic action [1].
History
The compound's odd pharmacology was first described by A. P. Roszkowski in 1961 in the Journal of Pharmacology and Experimental Therapeutics, reported there as an unusual sympathetic ganglionic stimulant: it raised blood pressure in cats and dogs, the rise was blocked by atropine but not by hexamethonium, and it disappeared after adrenalectomy and sympathectomy. When the muscarinic subtypes were cloned two decades later the ganglionic receptor was identified as M1, and McN-A-343 became the reference M1 agonist largely by default. The reassessment arrived from two directions: subtype panels showing flat affinity across M1 to M5, and the 2008 demonstration that the molecule acts bitopically at M2.
Reputation
Well known inside muscarinic pharmacology and essentially unknown outside it. Its standing has shifted from the M1-selective agonist to a worked example of how a partial agonist with uneven efficacy gets mistaken for a selective one, and of how allosteric and orthosteric pharmacology can coexist in one small molecule. Papers that still cite it as evidence of M1 involvement without addressing the efficacy argument are read with caution.
Subjective profileweighing the evidence above
A cautionary tale worth knowing before trusting any compound called selective. Thirty years of papers used it to assign responses to M1 receptors; the affinity measurements show it binding all five subtypes at roughly the same low micromolar strength, so the selectivity was never in the binding at all. The compound is still useful, but only when what it is actually doing gets stated correctly.
Resources
This entry is here for reference.
Research
- 1961first citedAn unusual type of sympathetic ganglionic stimulant.
- 2012most recentThe pharmacology of McN-A-343.
- 1.The pharmacology of McN-A-343.
- 2.A novel mechanism of G protein-coupled receptor functional selectivity. Muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand.
- 3.An unusual type of sympathetic ganglionic stimulant.
- 4.Pharmacologic comparison of selected agonists for the M1 muscarinic receptor in transfected murine fibroblast cells (B82).
- 5.Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias.
- 6.Structural determinants of allosteric agonism and modulation at the M4 muscarinic acetylcholine receptor: identification of ligand-specific and global activation mechanisms.
- 7.Compensation of muscarinic bronchial effects of talsaclidine by concomitant sympathetic activation in guinea pigs.
7 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is McN-A-343 actually M1-selective?
Not in binding. Its affinity for M1 through M5 falls in the same low micromolar band. What differs is efficacy, which is highest at M1 and M4, so in a tissue with plenty of spare receptors it looks selective and in a tissue without them it can behave as an antagonist against a fuller agonist.
What does bitopic mean?
A bitopic ligand occupies two sites on the same receptor at once: the orthosteric pocket where acetylcholine binds, and a separate allosteric site nearby. McN-A-343 does this at M2, and the allosteric half of the molecule shapes what the orthosteric half signals. Truncated fragments of it act as allosteric modulators with no agonist activity of their own.
Can I buy it or take it?
It is a laboratory reagent only. There is no human dose, no formulation and no indication. It does not enter the brain, and its main systemic action is to raise blood pressure through sympathetic ganglia.
Should older papers using it as an M1 probe be thrown out?
No, but they should be read with the efficacy argument in mind. A response that McN-A-343 produces is more likely M1 or M4 mediated than M2 or M3 mediated, which is a real and useful inference. What cannot be concluded is that the compound bound M1 preferentially, because it did not.
Adverse effects
- Bronchospasm in anaesthetised animals
- Pressor response and tachycardia
- Off-target 5-HT3 and 5-HT4 antagonism
- Local anaesthetic activity