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Xanomeline
Xanomeline (LY-246,708; Lumeron, Memcor) 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. Its pharmacological action is mediated primarily through stimulation of central nervous system muscarinic M1 and M4 receptor subtypes. Xanomeline is currently being developed as a combination drug (Kar-XT; xanomeline + trospium) by Karuna Therapeutics. Trospium is a non-CNS penetrant non-selective muscarinic antagonist to quell peripheral muscarinic agonist-dependent side effects. Xanomeline’s mechanism of action is hypothesized to be via rebalancing key neurotransmitter circuits, including acetylcholine, dopamine, and glutamate, which are disrupted in schizophrenia and related diseases. Chemistry Xanomeline has structural and pharmacological similarities to the main psychoactive ingredient i ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
KarXT
KarXT is an investigational oral dual-drug fixed-dose combination of xanomeline and Trospium chloride, trospium. It is undergoing a phase 3 clinical trial for the treatment of patients suffering from the symptoms of schizophrenia. Xanomeline is a functionally preferring Muscarinic acetylcholine receptor M4, muscarinic M4 and Muscarinic acetylcholine receptor M1, 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. Mechanism of action Preclinical data supports the hypothesis that xanomeline’s central mechanism of action is mediated primarily through stimulation of brain muscarinic M4 and M1 receptors. M4 muscarinic receptors are most highly expressed in the midbrain, which controls motor and action planning, decision-making, motivation, reinfor ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Muscarinic Agonists
A muscarinic agonist 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. Clinical significance M1 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. 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 ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Muscarinic Acetylcholine Receptor M1
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. This receptor is found mediating slow excitatory postsynaptic potential, EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS. It is predominantly found bound to G proteins of class Gq alpha subunit, Gq that use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway. A receptor so bound would not be susceptible to Cholera toxin, CTX or Pertussis toxin, PTX. However, Gi (causing a downstream decrease in Cyclic adenosine monophosphate, cAMP) and Gs (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX respectively. Effects *excitatory postsynaptic potential, EPSP in autonomic ganglia * Secret ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Muscarinic Acetylcholine Receptor
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. Muscarinic receptors are so named because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpine and scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists. Function Acetylcholine (ACh) is a neurotransmitter found in the brain, neuromuscular junctions and the autonomic ganglia. Muscarinic receptors are used in the following roles: Recovery receptors ACh is always used as ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Arecoline
Arecoline () is a nicotinic acid-based mild parasympathomimetic stimulant alkaloid found in the areca nut, the fruit of the areca palm (''Areca catechu''). It is an odourless oily liquid. It can bring a sense of enhanced alertness and energy, euphoria and relaxation. Its psychoactive effects are comparable to that of nicotine. Chemistry Arecoline is a base, and its conjugate acid has a pKa ~ 6.8. Arecoline is volatile in steam, miscible with most organic solvents and water, but extractable from water by ether in presence of dissolved salts. Being basic, arecoline forms salts with acids. The salts are crystalline, but usually deliquescent: the hydrochloride, arecoline•HCl, forms needles, m.p. 158 °C; the hydrobromide, arecoline•HBr, forms slender prisms, mp. 177–179 °C from hot alcohol; the aurichloride, arecoline•HAuCl4, is an oil, but the platinichloride, arecoline2•H2PtCl6, mp. 176 °C, crystallizes from water in orange-red rhombohedrons. The ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Vedaclidine
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. Synthesis : The Knoevenagel condensation between 3-Quinuclidone 731-38-2(1) & ethyl cyanoacetate 05-56-6(2) gives Ethyl (1-azabicyclo .2.2ctan-3-ylidine)cyanoacetateCID:54445383(3). The catalytic hydrogenation of the olefin group gave Ethyl (1-azabicyclo .2.2ctan-3-yl)cyanoacetate 41593-50-2(4). The reac ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Tazomeline
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". Synthesis : A Strecker type alpha-amino nitrile between nicotinaldehyde, potassium cyanide and ammonium chloride gives amino(pyridin-3-yl)acetonitrile 31988-63-1(2). The halogenation of this intermediate with sulfur monochloride 0025-67-9in DMF led to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole 31986-28-2(3). : Thioether formation with 1-Hexanethiol 11-31-9(4) in the presence of sodium hydrogen sulfide, DMF and K2CO3 gave 3-(4-hexylthio-1,2,5-thiadiazol-3-yl)pyridineCID:10755149(5). Alkylation with methyl iodide gives 3-(4-hexylthio-1,2,5-thiadiazol-3-yl)-1-methylpyridinium iodideCID:19075299(6). ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Sabcomeline
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 trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...s before being discontinued due to poor results. See also * Alvameline * Milameline * Tazomeline * Xanomeline References {{Muscarinic acetylcholine receptor modulators Muscarinic agonists Nitriles Oximes Quinuclidines Experimental drugs ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Milameline
Milameline (CI-979, PD-129,409, RU-35,926) 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. *Changing the ''O''-methyl aldoxime to an ''O''-propargyl oxime instead gives a separate molecule called RU 35986. See also * Alvameline * Sabcomeline * Tazomeline * Xanomeline Xanomeline (LY-246,708; Lumeron, Memcor) 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 treatme ... References {{Muscarinic acetylcholine receptor modulators Muscarinic agonists Aldoximes Tetrahydropyridines ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Alvameline
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. Synthesis Alkylation of nicotinonitrile (accessible from nicotinamide) (1) with methyl iodide affords the ''N''-methylpyridinium salt (2). The reduction of this intermediate with sodium borohydride gives 3-cyano-''N''-methyl-1,2,5,6- tetrahydropyridine 657-66-9(3). Reaction with ethyl chloroformate results in ''N''-demethylation and consequent formation of the corresponding carbamate 20241-16-9(4). The nitrile group is then transformed to a tetrazole by reaction with sodium azide in the presence of aluminum chloride givinCID:9991151(5). The surrogate acid is then alkylated with ethyl iodide to afforCID:10106197(6). Treatment with acid then removes the carbamate on the ring nitrogen giving Lu-25-077 21549-70-8(7). The methyl group on the pip ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Hydrogen Bond
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a lone pair of electrons—the hydrogen bond acceptor (Ac). Such an interacting system is generally denoted , where the solid line denotes a polar covalent bond, and the dotted or dashed line indicates the hydrogen bond. The most frequent donor and acceptor atoms are the second-row elements nitrogen (N), oxygen (O), and fluorine (F). Hydrogen bonds can be intermolecular (occurring between separate molecules) or intramolecular (occurring among parts of the same molecule). The energy of a hydrogen bond depends on the geometry, the environment, and the nature of the specific donor and acceptor atoms and can vary between 1 and 40 kcal/mol. This makes them somewhat stronger than a van der Waals interaction, and weaker than fully covalent o ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdrawal, decreased emotional expression, and apathy. Symptoms typically develop gradually, begin during young adulthood, and in many cases never become resolved. There is no objective diagnostic test; diagnosis is based on observed behavior, a history that includes the person's reported experiences, and reports of others familiar with the person. To be diagnosed with schizophrenia, symptoms and functional impairment need to be present for six months ( DSM-5) or one month (ICD-11). Many people with schizophrenia have other mental disorders, especially substance use disorders, depressive disorders, anxiety disorders, and obsessive–compulsive disorder. About 0.3% to 0.7% of people are diagnosed with schizophrenia during their lifetim ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
