|
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] |
Alvameline Synthesis
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] |
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] |
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] |
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] |
Tetrazole
Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen atoms and one carbon atom. The name tetrazole also refers to the parent compound with formula CH2N4, of which three isomers can be formulated. Structure and bonding Three isomers of the parent tetrazole exist, differing in the position of the double bonds: 1''H''-, 2''H''-, and 5''H''-tetrazole. The 1''H''- and 2''H''- isomers are tautomers, with the equilibrium lying on the side of 1''H''-tetrazole in the solid phase. In the gas phase, 2''H''-tetrazole dominates. These isomers can be regarded as aromatic, with 6 π-electrons, while the 5''H''-isomer is nonaromatic. Synthesis 1''H''-Tetrazole was first prepared by the reaction of anhydrous hydrazoic acid and hydrogen cyanide under pressure. Treatment of organic nitriles with sodium azide in the presence of iodine or silica-supported sodium bisulfate as a heterogeneous catalyst enables an advantageous synthesis o ... [...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] |
Eschweiler–Clarke Reaction
The Eschweiler–Clarke reaction (also called the Eschweiler–Clarke methylation) is a chemical reaction whereby a primary (or secondary) amine is methylated using excess formic acid and formaldehyde. Reductive amination reactions such as this one will not produce quaternary ammonium salts, but instead will stop at the tertiary amine stage. It is named for the German chemist Wilhelm Eschweiler (1860–1936) and the British chemist Hans Thacher Clarke (1887-1972). Mechanism The reaction is generally performed in an aqueous solution at close to boiling. The first methylation of the amine begins with imine formation with formaldehyde. The formic acid acts as a source of hydride and reduces the imine to a secondary amine. Loss of carbon dioxide gas renders the reaction irreversible. Despite being more hindered, the formation of the tertiary amine is more favorable, as the intermediate in iminium ion is formed without needing to protonate. Hence the treatment of a primary amine wit ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Formic Acid
Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid, and has the chemical formula HCOOH and structure . It is an important intermediate in chemical synthesis and occurs naturally, most notably in some ants. Esters, salts and the anion derived from formic acid are called formates. Industrially, formic acid is produced from methanol. Natural occurrence In nature, formic acid is found in most ants and in stingless bees of the genus ''Oxytrigona''. Wood ants from the genus ''Formica'' can spray formic acid on their prey or to defend the nest. The puss moth caterpillar (''Cerura vinula'') will spray it as well when threatened by predators. It is also found in the trichomes of stinging nettle (''Urtica dioica''). Apart from that, this acid is incorporated in many fruits such as pineapple (0.21mg per 100g), apple (2mg per 100g) and kiwi (1mg per 100g), as well as in many vegetables, namely onion (45mg per 100g), eggplant (1.34 mg per 100g) and, ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section Forms below), hence it is stored as an aqueous solution (formalin), which is also used to store animal specimens. It is the simplest of the aldehydes (). The common name of this substance comes from its similarity and relation to formic acid. Formaldehyde is an important precursor to many other materials and chemical compounds. In 1996, the installed capacity for the production of formaldehyde was estimated at 8.7 million tons per year. It is mainly used in the production of industrial resins, e.g., for particle board and coatings. Forms Formaldehyde is more complicated than many simple carbon compounds in that it adopts several diverse forms. These compounds can often be used interchangeably and can be interconverted. *Molecular forma ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Piperidine
Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor described as objectionable, and typical of amines. The name comes from the genus name '' Piper'', which is the Latin word for pepper. Although piperidine is a common organic compound, it is best known as a representative structure element within many pharmaceuticals and alkaloids, such as natural-occurring solenopsins. Production Piperidine was first reported in 1850 by the Scottish chemist Thomas Anderson and again, independently, in 1852 by the French chemist Auguste Cahours, who named it. Both of them obtained piperidine by reacting piperine with nitric acid. Industrially, piperidine is produced by the hydrogenation of pyridine, usually over a molybdenum disulfide catalyst: : C5H5N + 3 H2 → C5H10NH Pyridine can also be redu ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
