| Muscarinic agonist | |
|---|---|
| Drug class | |
 | |
| Class identifiers | |
| ATC code | N07 |
| Biological target | muscarinic acetylcholine receptor |
| External links | |
| MeSH | D018721 |
| Legal status | |
| In Wikidata | |
A muscarinic agonist [1] is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, labelled M1-M5, allowing for further differentiation.
M1-type muscarinic acetylcholine receptors play a role in cognitive processing. In Alzheimer 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 agent xanomeline has been proposed as a potential treatment for schizophrenia. [5] [6]
In the form of pilocarpine, muscarinic receptor agonists have been used medically for a short time.
| Comparison of cholinergic agonists [7] | ||||
|---|---|---|---|---|
| Substance | Receptor specificity | Hydrolysis by acetylcholinesterase | Comments | |
| Muscarinic | Nicotinic | |||
| Acetylcholine | +++ | +++ | +++ | Endogenous ligand |
| Carbachol | ++ | +++ | - | Used in the treatment of glaucoma |
| Methacholine | +++ | + | ++ | Used to diagnose bronchial hyperreactivity, [8] a hallmark of asthma and COPD. |
| Bethanechol | +++ | - | - | Used in bladder and gastrointestinal hypotonia. |
| Muscarine | +++ | - | - | Natural alkaloid found in certain mushrooms. Cause of one form of mushroom poisoning |
| Nicotine | - | +++ | - | Natural alkaloid found in the tobacco plant. |
| Pilocarpine | ++ | - | - | Used in glaucoma. |
| Oxotremorine | ++ | + [9] | - | Used in research to induce symptoms of Parkinson's disease. |
 | This section needs expansion. You can help by adding to it. (April 2019) |
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.
Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested. Muscarine has been found in harmless trace amounts in Boletus, Hygrocybe, Lactarius and Russula. Trace concentrations of muscarine are also found in Amanita muscaria, though the pharmacologically more relevant compound from this mushroom is the Z-drug-like alkaloid muscimol. A. muscaria fruitbodies contain a variable dose of muscarine, usually around 0.0003% fresh weight. This is very low and toxicity symptoms occur very rarely. Inocybe and Clitocybe contain muscarine concentrations up to 1.6%.
A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acetylcholine (ACh) is the neurotransmitter used by the PSNS. Chemicals in this family can act either directly by stimulating the nicotinic or muscarinic receptors, or indirectly by inhibiting cholinesterase, promoting acetylcholine release, or other mechanisms. Common uses of parasympathomimetics include glaucoma, Sjögren syndrome and underactive bladder.
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.
Arecoline is a nicotinic acid-based mild parasympathomimetic stimulant alkaloid found in the areca nut, the fruit of the areca palm. It is an odourless oily liquid. It can bring a sense of enhanced alertness and energy along with mild feelings of euphoria and relaxation. The psychoactive effects are comparable to that of nicotine.
A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work to prevent this transmission from occurring. Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal. Muscarinic antagonists counter this parasympathetic "rest-and-digest" response, and also work elsewhere in both the central and peripheral nervous systems.
A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.
The human muscarinic acetylcholine receptor M5, encoded by the CHRM5 gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to Gq protein. Binding of the endogenous ligand acetylcholine to the M5 receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).
The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor that in humans is encoded by the CHRM1 gene. It is localized to 11q13.
GTS-21 is an investigational drug that has been studied for its potential therapeutic uses, particularly in the treatment of neurodegenerative diseases and psychiatric disorders.
Xanomeline is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system disorders.
Vedaclidine (INN, codenamed LY-297,802, NNC 11-1053) is an experimental analgesic drug which acts as a mixed agonist–antagonist at muscarinic acetylcholine receptors, being a potent and selective agonist for the M1 and M4 subtypes, yet an antagonist at the M2, M3 and M5 subtypes. It is orally active and an effective analgesic over 3× the potency of morphine, with side effects such as salivation and tremor only occurring at many times the effective analgesic dose. Human trials showed little potential for development of dependence or abuse, and research is continuing into possible clinical application in the treatment of neuropathic pain and cancer pain relief.
Alvameline (Lu 25-109) is a M1 receptor agonist and M2/M3 receptor antagonist that was under investigation for the treatment of Alzheimer's disease, but produced poor results in clinical trials and was subsequently discontinued.
Milameline is a non-selective muscarinic acetylcholine receptor partial agonist with cognition-acting properties that was being investigated for the treatment of Alzheimer's disease, but produced poor results in clinical trials and was subsequently discontinued.
Tazomeline (LY-287,041) is a drug which acts as a non-selective muscarinic acetylcholine receptor agonist. It was in clinical trials for the treatment of cognitive dysfunction such as that seen in Alzheimer's disease and schizophrenia, but development was apparently scrapped for unknown reasons. Another of the patented uses is for the treatment of "severe painful conditions".
CI-1017 is a muscarinic acetylcholine receptor agonist which is selective for and is approximately equipotent at the M1 and M4 receptors, with 20-30-fold lower affinity for the M2, M3, and M5 subtypes It is the (R)-enantiomer of the racemic compound PD-142,505.
Blarcamesine is an experimental drug developed by Anavex Life Sciences.
Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.
KarXT is an investigational oral dual-drug fixed-dose combination of xanomeline and trospium. It is undergoing a phase 3 clinical trial for the treatment of schizophrenia. Xanomeline is a functionally preferring muscarinic M4 and M1 receptor agonist that readily passes into the central nervous system (CNS) to stimulate these receptors in key areas of the brain. Trospium is a non-selective muscarinic antagonist that does not cross into the CNS and reduces peripheral cholinergic side effects associated with xanomeline.