Muscarinic agonist

Short description: Activator of the muscarinic acetylcholine receptor

Muscarinic agonist

Drug class

Skeletal structure formula of muscarine

Class identifiers
Synonyms| Muscarinic acetylcholine receptor agonist; Muscarinic receptor agonist; Muscarinic; Muscarinic drug; Muscarinic agent; Muscarinic medication; mACh agonist; mAChR agonist
ATC code| N07
Biological target| muscarinic acetylcholine receptor
External links
MeSH| D018721

A muscarinic acetylcholine receptor agonist, also known as a muscarinic agonist or as a muscarinic agent, is an agent that activates the muscarinic acetylcholine receptor.[1] The muscarinic receptor has different subtypes, labelled M1-M5, allowing further differentiation.

## Contents

* 1 Clinical significance
* 1.1 M1
* 1.2 M3
* 1.3 M4
* 2 Muscarinic versus nicotinic activity
* 3 Muscarinic acetylcholine receptor subtypes
* 4 See also
* 5 References
* 6 External links

## Clinical significance

### M1

M1-type muscarinic acetylcholine receptors play a role in cognitive processing. In Alzheimer's disease (AD), amyloid formation may decrease the ability of these receptors to transmit signals, leading to decreased cholinergic activity. As these receptors themselves appear relatively unchanged in the disease process, they have become a potential therapeutic target when trying to improve cognitive function in patients with AD.[2][3][4]

A number of muscarinic agonists have been developed and are under investigation to treat AD. These agents show promise as they are neurotrophic, decrease amyloid depositions, and improve damage due to oxidative stress. Tau-phosphorylation is decreased and cholinergic function enhanced. Notably several agents of the AF series of muscarinic agonists have become the focus of such research:. AF102B, AF150(S), AF267B. In animal models that are mimicking the damage of AD, these agents appear promising.

The dual M1, M4 agonist xanomeline has been proposed as a potential treatment for schizophrenia.[5][6] Xanomeline/trospium chloride was approved in the US in 2024.[7] Based on preclinical pharmacological and genetic studies, M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.[8]

### M3

In the form of pilocarpine, muscarinic receptor agonists have been used medically for a short time.

* M3 agonists
* Aceclidine, for glaucoma
* Arecoline, an alkaloid present in the Betel nut
* Pilocarpine, a drug that acts as a muscarinic receptor agonist that is used to treat glaucoma
* Cevimeline (AF102B, Evoxac), a muscarinic agonist that is a Food and Drug Administration-approved drug and used for the management of dry mouth in Sjögren's syndrome

### M4

Xanomeline exerts its action partially through the M4 receptor. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate both psychosis and cognitive symptom domains.[9][8]

## Muscarinic versus nicotinic activity

Comparison of cholinergic agonists[10] Substance  | Receptor specificity  | Hydrolysis
by AChE | Comments

|
|
|

Muscarinic  | Nicotinic
Acetylcholine | High | High | High | Endogenous ligand.
Carbachol | Moderate | High | None | Used in the treatment of glaucoma.
Methacholine | High | Low | Moderate | Used to diagnose bronchial hyperreactivity,[11] a hallmark of asthma and COPD.
Bethanechol | High | None | None | Used in bladder and gastrointestinal hypotonia.
Muscarine | High | None | None | Natural alkaloid found in certain mushrooms. Cause of one form of mushroom poisoning.
Nicotine | None | High | None | Natural alkaloid found in the tobacco plant.
Pilocarpine | Moderate | None | None | Used in glaucoma.
Oxotremorine | Moderate | Low[12] | None | Used in research to induce symptoms of Parkinson's disease.

## Muscarinic acetylcholine receptor subtypes

The targets for muscarinic agonists are the muscarinic receptors: M1, M2, M3, M4 and M5. These receptors are GPCRs coupled to either Gi or Gq subunits.

## See also

* Muscarine
* Muscarinic acetylcholine receptor
* Muscarinic antagonist
* Nicotinic acetylcholine receptor
* Nicotinic agonist
* Nicotinic antagonist

## References

1. ↑ Broadley, Kenneth J.; Kelly, David R. (2001-02-28). "Muscarinic Receptor Agonists and Antagonists". Molecules 6 (3): 142–193. doi:10.3390/60300142. ISSN 1420-3049.
2. ↑ "AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease". J Mol Neurosci 19 (1–2): 145–53. 2002. doi:10.1007/s12031-002-0025-3. PMID 12212772.
3. ↑ "M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease". Drug Development Research 50 (3–4): 291–297. 2000. doi:10.1002/1098-2299(200007/08)50:3/4<291::aid-ddr12>3.0.co;2-6.
4. ↑ Fisher A (July 2008). "Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer's disease". Neurotherapeutics 5 (3): 433–42. doi:10.1016/j.nurt.2008.05.002. PMID 18625455.
5. ↑ "Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia". Am J Psychiatry 165 (8): 1033–9. July 2008. doi:10.1176/appi.ajp.2008.06091591. PMID 18593778.
6. ↑ "Muscarinic agonists for the treatment of cognition in schizophrenia". CNS Spectrums 13 (1): 985–96. November 2008. doi:10.1017/S1092852900014048. PMID 19037177.
7. ↑ "U.S. Food and Drug Administration Approves Bristol Myers Squibb's Cobenfy (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults" (Press release). Bristol Myers Squibb. 27 September 2024. Retrieved 27 September 2024 - via Business Wire.
8. ↑ 8.0 8.1 "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". The American Journal of Psychiatry 179 (9): 611–627. September 2022. doi:10.1176/appi.ajp.21101083. PMID 35758639.
9. ↑ "Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice". European Journal of Pharmacology 603 (1–3): 147–149. January 2009. doi:10.1016/j.ejphar.2008.12.020. PMID 19111716.
10. ↑ Rang, Humphrey P.; Dale, Maureen M.; Ritter, James M.; Flower, Rod J. (2007). Rang and Dale's Pharmacology (6th ed.). Edinburgh: Churchill Livingstone. p. 152. ISBN 978-0-443-06911-6. https://archive.org/details/rangdalespharmac0006dale/page/152/mode/2up.
11. ↑ "Methacholine challenge testing: identifying its diagnostic role, testing, coding, and reimbursement". Chest 131 (6): 1932–5. June 2007. doi:10.1378/chest.06-1385. PMID 17565027. https://journal.chestnet.org/article/S0012-3692(15)37533-4/fulltext.
12. ↑ Akk, Gustav; Auerbach, Anthony (1999-12-01). "Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists". British Journal of Pharmacology 128 (7): 1467–1476. doi:10.1038/sj.bjp.0702941. ISSN 0007-1188. PMID 10602325.

## External links

* Muscarinic+Agonists at the US National Library of Medicine Medical Subject Headings (MeSH)

* v
* t
* e

Pharmacomodulation

Types|

* ♦ Enzyme: Inducer
* Inhibitor

* ♦ Ion channel: Opener
* Blocker

* ♦ Receptor: Agonist
* Partial agonist
* Antagonist
* Inverse agonist
* Positive allosteric modulator (PAM)
* Negative allosteric modulator (NAM)

* ♦ Transporter [Reuptake vs Efflux]: Enhancer (RE)
* Inhibitor (RI)
* Releaser (RA)

* ♦ Miscellaneous: Precursor
* Cofactor

Classes|

| Enzyme|

see Enzyme inhibition

|

Ion channel|

See Ion channel modulators

Receptor &
transporter|

| BA/M|

| Adrenergic|

* Adrenergic receptor agonist (α
* β (1
* 2))
* Adrenergic receptor antagonist (α (1
* 2)
* β)
* Norepinephrine reuptake inhibitor (NRI)

|

Dopaminergic|

* Dopamine receptor agonist
* Dopamine receptor antagonist
* Dopamine reuptake inhibitor (DRI)

Histaminergic|

* Histamine receptor agonist
* Histamine receptor antagonist (H1
* H2
* H3)

Serotonergic|

* Serotonin receptor agonist
* Serotonin receptor antagonist (5-HT3)
* Serotonin reuptake inhibitor (SRI)

AA|

| GABAergic|

* GABA receptor agonist
* GABA receptor antagonist
* GABA reuptake inhibitor (GRI)

|

Glutamatergic|

* Glutamate receptor agonist (AMPA)
* Glutamate receptor antagonist (NMDA)
* Glutamate reuptake inhibitor

Cholinergic|

* Acetylcholine receptor agonist (Muscarinic
* Nicotinic)
* Acetylcholine receptor antagonist (Muscarinic
* Nicotinic (Ganglionic
* Muscular))

Cannabinoidergic|

* Cannabinoid receptor agonist
* Cannabinoid receptor antagonist
* Endocannabinoid enhancer (eCBE)
* Endocannabinoid reuptake inhibitor (eCBRI)

Opioidergic|

* Opioid modulator
* Opioid receptor agonist
* Opioid receptor antagonist
* Enkephalinase inhibitor

Other|

* Adenosine reuptake inhibitor (AdoRI)
* Angiotensin II receptor antagonist
* Endothelin receptor antagonist
* NK1 receptor antagonist
* Vasopressin receptor antagonist

Miscellaneous|

* Cofactor (see Enzyme cofactors)
* Precursor (see Amino acids)

Acetylcholine receptor modulators

* v
* t
* e

Muscarinic acetylcholine receptor modulators

mAChRs|

| Agonists|

* 77-LH-28-1
* AC-42
* AC-260,584
* Aceclidine
* Acetylcholine
* AF30
* AF150(S)
* AF267B
* Alvameline
* AQRA-741
* Arecoline
* Bethanechol
* Bevonium
* Butyrylcholine
* Carbachol
* CDD-0034
* CDD-0078
* CDD-0097
* CDD-0098
* CDD-0102
* Cevimeline
* Choline
* cis-Dioxolane
* Clozapine
* Desmethylclozapine (norclozapine)
* Ethoxysebacylcholine
* Itameline
* LY-593,039
* L-689,660
* LY-2,033,298
* McNA343
* Methacholine
* Milameline
* Muscarine
* NGX-267
* Ocvimeline
* Oxotremorine
* PD-151,832
* Pilocarpine
* RS86
* Sabcomeline
* SDZ 210-086
* Sebacylcholine
* Suberyldicholine
* Talsaclidine
* Tazomeline
* Thiopilocarpine
* Vedaclidine
* VU-0029767
* VU-0090157
* VU-0152099
* VU-0152100
* VU-0238429
* WAY-132,983
* Xanomeline
* YM-796

|

Antagonists|

* 3-Quinuclidinyl benzilate
* 4-DAMP
* Aclidinium bromide (+formoterol)
* Abediterol
* AF-DX 250
* AF-DX 384
* Ambutonium bromide
* Anisodamine
* Anisodine
* Antihistamines (first-generation) (e.g., brompheniramine, buclizine, captodiame, chlorphenamine (chlorpheniramine), cinnarizine, clemastine, cyproheptadine, dimenhydrinate, [[Chemistry:Dimetdimetindene, Diphenhydramine|diphenhydramine]], doxylamine, meclizine, mepyramine (pyrilamine), mequitazine, perlapine, phenindamine, pheniramine, Phenyltoloxamine|Phenyltoloxamine]]]], promethazine, propiomazine, triprolidine)
* AQ-RA 741
* Atropine
* Atropine methonitrate
* Atypical antipsychotics (e.g., clozapine, Chemistry:Fluperlapine

Precursors
(and prodrugs)|

* Acetyl-coA
* Adafenoxate
* Choline (lecithin)
* Citicoline
* Cyprodenate
* Dimethylethanolamine
* Glycerophosphocholine
* Meclofenoxate (centrophenoxine)
* Phosphatidylcholine
* Phosphatidylethanolamine
* Phosphorylcholine
* Pirisudanol

See also: Receptor/signaling modulators • Nicotinic acetylcholine receptor modulators • Acetylcholine metabolism/transport modulators

* v
* t
* e

Nicotinic acetylcholine receptor modulators

nAChRs|

| Agonists
(and PAMs)|

* 5-HIAA
* A-84,543
* A-366,833
* A-582,941
* A-867,744
* ABT-202
* ABT-418
* ABT-560
* ABT-894
* Acetylcholine
* Altinicline
* Anabasine
* Anatoxin-a
* AR-R17779
* Bephenium hydroxynaphthoate
* Butinoline
* Butyrylcholine
* Carbachol
* Choline
* Cotinine
* Cytisine
* Decamethonium
* Desformylflustrabromine
* Dianicline
* Dimethylphenylpiperazinium
* Epibatidine
* Epiboxidine
* Ethanol (alcohol)
* Ethoxysebacylcholine
* EVP-4473
* EVP-6124
* Galantamine
* GTS-21
* Ispronicline
* Ivermectin
* JNJ-39393406
* Levamisole
* Lobeline
* MEM-63,908 (RG-3487)
* Morantel
* Nicotine (tobacco)
* NS-1738
* PHA-543,613
* PHA-709,829
* PNU-120,596
* PNU-282,987
* Pozanicline
* Pyrantel
* Rivanicline
* RJR-2429
* Sazetidine A
* SB-206553
* Sebacylcholine
* SIB-1508Y
* SIB-1553A
* SSR-180,711
* Suberyldicholine
* Suxamethonium (succinylcholine)
* Suxethonium (succinyldicholine)
* TC-1698
* TC-1734
* TC-1827
* TC-2216
* TC-5214
* TC-5619
* TC-6683
* Tebanicline
* Tribendimidine
* Tropisetron
* UB-165
* Varenicline
* WAY-317,538
* XY-4083

|

Antagonists
(and NAMs)|

* 18-MAC
* 18-MC
* α-Neurotoxins (e.g., α-bungarotoxin, α-cobratoxin, α-conotoxin, many others)
* ABT-126
* Alcuronium
* Allopregnanolone
* Amantadine
* Anatruxonium
* AQW051
* Atracurium
* Barbiturates (e.g., pentobarbital, sodium thiopental)
* BNC-210
* Bungarotoxins (e.g., α-bungarotoxin, κ-bungarotoxin)
* Bupropion
* BW284C51
* BW-A444
* Candocuronium iodide (chandonium iodide)
* Chlorisondamine
* Cisatracurium
* Coclaurine
* Coronaridine
* Curare
* Cyclopropane
* Dacuronium bromide
* Decamethonium
* Dehydronorketamine
* Desflurane
* Dextromethorphan
* Dextropropoxyphene
* Dextrorphan
* Diadonium
* DHβE
* Dihydrochandonium
* Dimethyltubocurarine (metocurine)
* Dioscorine
* Dipyrandium
* Dizocilpine (MK-801)
* Doxacurium
* Encenicline
* Enflurane
* Erythravine
* Esketamine
* Fazadinium
* Gallamine
* Gantacurium chloride
* Halothane
* Hexafluronium
* Hexamethonium (benzohexonium)
* Hydroxybupropion
* Hydroxynorketamine
* Ibogaine
* Isoflurane
* Ketamine
* Kynurenic acid
* Laudanosine
* Laudexium (laudolissin)
* Levacetylmethadol
* Levomethadone
* Malouetine
* ME-18-MC
* Mecamylamine
* Memantine
* Methadone
* Methorphan (racemethorphan)
* Methyllycaconitine
* Metocurine
* Mivacurium
* Morphanol (racemorphan)
* Neramexane
* Nitrous oxide
* Norketamine
* Pancuronium bromide
* Pempidine
* Pentamine
* Pentolinium
* Phencyclidine
* Pipecuronium bromide
* Progesterone
* Promegestone
* Radafaxine
* Rapacuronium bromide
* Reboxetine
* Rocuronium bromide
* Sevoflurane
* Stercuronium iodide
* Surugatoxin
* Thiocolchicoside
* Toxiferine
* Tramadol
* Trimetaphan camsilate (trimethaphan camsylate)
* Tropeinium
* Tubocurarine
* Vanoxerine
* Vecuronium bromide
* Xenon

Precursors
(and prodrugs)|

* Acetyl-coA
* Adafenoxate
* Choline (lecithin)
* Citicoline
* Cyprodenate
* Dimethylethanolamine
* Glycerophosphocholine
* Meclofenoxate (centrophenoxine)
* Phosphatidylcholine
* Phosphatidylethanolamine
* Phosphorylcholine
* Pirisudanol

See also: Receptor/signaling modulators • Muscarinic acetylcholine receptor modulators • Acetylcholine metabolism/transport modulators

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*[mAChRs]: Muscarinic acetylcholine receptors
*[nAChRs]: Nicotinic acetylcholine receptors
*[PAMs]: positive allosteric modulators
*[NAMs]: negative allosteric modulators