Itameline

Last updated

Itameline
Clinical data
Other namesRU-47213; RU47213
Drug class Non-selective muscarinic acetylcholine receptor agonist
Identifiers
  • (4-chlorophenyl) 5-[(E)-methoxyiminomethyl]-3,6-dihydro-2H-pyridine-1-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C14H15ClN2O3
Molar mass 294.74 g·mol−1
3D model (JSmol)
  • CO/N=C/C1=CCCN(C1)C(=O)OC2=CC=C(C=C2)Cl
  • InChI=1S/C14H15ClN2O3/c1-19-16-9-11-3-2-8-17(10-11)14(18)20-13-6-4-12(15)5-7-13/h3-7,9H,2,8,10H2,1H3/b16-9+
  • Key:CTVQNEVLCGSTKL-CXUHLZMHSA-N

Itameline (INN Tooltip International Nonproprietary Name; developmental code name RU-47213) is a non-selective muscarinic acetylcholine receptor agonist which was under development for the treatment of Alzheimer's disease and memory disorders but was never marketed. [1] [2] [3] It has been referred to as a "nootropic" (cognitive enhancer). [4] [5]

The drug is a prodrug of RU-35963, an arecoline derivative. [6] [7] [2] It is an agonist of the muscarinic acetylcholine M1 receptor as well as of other muscarinic acetylcholine receptors. [8] [6] [9] [7] [2] Itameline is described as being superior to arecoline in terms of potency, central selectivity, and duration of action. [6] [7] The drug shows antiamnesic effects in animals, for instance reversing scopolamine-induced memory deficits. [10] [6] [2] [3] Structurally, it is a tetrahydropyridine similarly to xanomeline and milameline. [11]

Itameline was first described in the scientific literature by 1992. [3] It was under development by Hoechst Marion Roussel and reached phase 2 clinical trials by 1998 prior to the discontinuation of its development. [12] [7] [4]

Related Research Articles

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

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.

<span class="mw-page-title-main">Cholinergic</span> Agent which mimics choline

Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin. Choline also prevents fat deposits in the liver and facilitates the movement of fats into cells.

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.

<span class="mw-page-title-main">Muscarinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of muscarine

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. They are mainly found in the parasympathetic nervous system, but also have a role in the sympathetic nervous system in the control of sweat glands.

<span class="mw-page-title-main">Arecoline</span> Stimulant alkaloid

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.

<span class="mw-page-title-main">Muscarinic agonist</span> Activating agent of the muscarinic acetylcholine receptor

A muscarinic acetylcholine receptor agonist, also simply known as a muscarinic agonist or as a muscarinic agent, 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.

<span class="mw-page-title-main">Muscarinic antagonist</span> Drug that binds to but does not activate muscarinic cholinergic receptors

A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarinic receptors are proteins 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.

Muscarinic acetylcholine receptor M<sub>1</sub> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">ABT-418</span> Chemical compound

ABT-418 is a drug developed by Abbott, that has nootropic, neuroprotective and anxiolytic effects, and has been researched for treatment of both Alzheimer's disease and ADHD. It acts as an agonist at neural nicotinic acetylcholine receptors, subtype-selective binding with high affinity to the α4β2, α7/5-HT3, and α2β2 nicotinic acetylcholine receptors but not α3β4 receptors ABT-418 was reasonably effective for both applications and fairly well tolerated, but produced some side effects, principally nausea, and it is unclear whether ABT-418 itself will proceed to clinical development or if another similar drug will be used instead.

<span class="mw-page-title-main">GTS-21</span> Chemical compound

GTS-21 is a drug that has been shown to enhance memory and cognitive function. It has been studied for its potential therapeutic uses, particularly in the treatment of neurodegenerative diseases and psychiatric disorders.

<span class="mw-page-title-main">Xanomeline</span> Chemical compound

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 (CNS) disorders.

<span class="mw-page-title-main">Vedaclidine</span> Chemical compound

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.

<span class="mw-page-title-main">Milameline</span> Chemical compound

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.

<span class="mw-page-title-main">Sabcomeline</span> Chemical compound

Sabcomeline (Memric; SB-202,026) is a selective M1 receptor partial agonist that was under development for the treatment of Alzheimer's disease. It made it to phase III clinical trials before being discontinued due to poor results.

<span class="mw-page-title-main">Tazomeline</span> Chemical compound

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.

<span class="mw-page-title-main">Blarcamesine</span> Medication

Blarcamesine is an experimental drug which is under development for the treatment of Alzheimer's disease and a variety of other indications.

<span class="mw-page-title-main">Xanomeline/trospium chloride</span> Medication

Xanomeline/trospium chloride, sold under the brand name Cobenfy, is a fixed-dose combination medication used for the treatment of schizophrenia. It contains xanomeline, a muscarinic agonist; and trospium chloride, a muscarinic antagonist. Xanomeline is a functionally preferring muscarinic M4 and M1 receptor agonist. Trospium chloride is a non-selective muscarinic antagonist.

Revosimeline is a muscarinic acetylcholine receptor agonist which has not been marketed at this time. It is said to be an agonist of the muscarinic acetylcholine M1 receptor. The drug appears to be structurally distinct from earlier muscarinic acetylcholine receptor agonists like milameline and xanomeline. Its INNTooltip International Nonproprietary Name was designated in 2018.

References

  1. ↑ "Delving into the Latest Updates on Itameline with Synapse". Synapse. 28 September 2024. Retrieved 26 October 2024.
  2. 1 2 3 4 M'Harzi M, Willig F, Gieules C, Palou AM, Oberlander C, Barzaghi F (April 1997). "Ameliorating effects of RU 47213, a novel oral and long-lasting cholinomimetic agent, on working memory impairments in rats". Pharmacology, Biochemistry, and Behavior. 56 (4): 663–668. doi:10.1016/s0091-3057(96)00423-6. PMID   9130292.
  3. 1 2 3 Toja E, Bonetti C, Butti A, Hunt P, Fortin M, Barzaghi F, et al. (1992). "1-substituted-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-alkyloximes as novel orally active and long-lasting muscarinic cholinergic agonists". European Journal of Medicinal Chemistry. 27 (5). Elsevier BV: 519–526. doi:10.1016/0223-5234(92)90186-5. ISSN   0223-5234.
  4. 1 2 Froestl W, Muhs A, Pfeifer A (2012). "Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors". Journal of Alzheimer's Disease. 32 (4): 793–887. doi:10.3233/JAD-2012-121186. PMID   22886028.
  5. ↑ Fischer F, Matthisson M, Herrling P (2004). "List of drugs in development for neurodegenerative diseases". Neuro-Degenerative Diseases. 1 (1): 50–70. doi:10.1159/000077879. PMID   16908974.
  6. 1 2 3 4 Camps P, Muñoz-Torrero D (February 2002). "Cholinergic drugs in pharmacotherapy of Alzheimer's disease". Mini Reviews in Medicinal Chemistry. 2 (1): 11–25. doi:10.2174/1389557023406638. PMID   12369954.
  7. 1 2 3 4 Saklani A, Kutty SK (February 2008). "Plant-derived compounds in clinical trials". Drug Discovery Today. 13 (3–4): 161–171. doi:10.1016/j.drudis.2007.10.010. PMID   18275914.
  8. ↑ Palma JA (February 2024). "Muscarinic control of cardiovascular function in humans: a review of current clinical evidence". Clinical Autonomic Research. 34 (1): 31–44. doi:10.1007/s10286-024-01016-5. PMC   10994193 . PMID   38305989.
  9. ↑ Korczyn AD (October 2000). "Muscarinic M(1) agonists in the treatment of Alzheimer's disease". Expert Opinion on Investigational Drugs. 9 (10): 2259–2267. doi:10.1517/13543784.9.10.2259. PMID   11060805.
  10. ↑ Deiana S, Platt B, Riedel G (August 2011). "The cholinergic system and spatial learning". Behavioural Brain Research. 221 (2): 389–411. doi:10.1016/j.bbr.2010.11.036. PMID   21108971.
  11. ↑ Mirza NR, Peters D, Sparks RG (2003). "Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists". CNS Drug Reviews. 9 (2): 159–186. doi:10.1111/j.1527-3458.2003.tb00247.x. PMC   6741650 . PMID   12847557.
  12. ↑ Eglen RM, Hegde SS (1998). "Selective modulation of muscarinic receptor subtypes: therapeutic potential". Emerging Drugs. 3 (1). Informa Healthcare: 67–80. doi:10.1517/14728214.3.1.67. ISSN   1361-9195.
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