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Xanomeline (LY-246,708; Lumeron, Memcor) ксаномелин , كسانوميلين , 诺美林 ,

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Xanomeline (LY-246,708LumeronMemcor)

CAS 131986-45-3

  • Molecular FormulaC14H23N3OS
  • Average mass281.417 Da
ксаномелин كسانوميلين 诺美林 
Hexyloxy-TZTP
5-[4-(Hexyloxy)-1,2,5-thiadiazol-3-yl]-1-méthyl-1,2,3,6-tétrahydropyridine
Xanomeline(LY246708) is a selective M1 muscarinic receptor agonist.
Pyridine, 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methyl-
Xanomeline(LY246708) is a selective M1 muscarinic receptor agonist. in vitro: Xanomeline had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for a number of other neurotransmitter receptors and uptake sites. In cells stably expressing genetic m1 receptors, xanomeline increased phospholipid hydrolysis in CHO, BHK and A9 L cells to 100, 72 and 55% of the nonselective agonist carbachol. In isolated tissues, xanomeline had high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.006 nM), low affinity for M2 receptors in guinea pig atria (EC50 = 3 microM), was a weak partial agonist in guinea pig ileum and was neither an agonist nor antagonist in guinea pig bladder. Xanomeline produced small increases in striatal acetylcholine levels and did not antagonize the large increases in acetylcholine produced by the nonselective muscarinic agonist oxotremorine, indicating that xanomeline did not block M2 autoreceptors. in vivo: Xanomeline increased striatal levels of dopamine metabolites, presumably by acting at M1 heteroreceptors on dopamine neurons to increase dopamine release. In contrast, xanomeline had only a relatively small effect on acetylcholine levels in brain, indicating that it is devoid of actions at muscarinic autoreceptors. The effects of xanomeline on ex vivo binding and DOPAC levels lasted for about 3 hr and were evident after oral administration. An analog of xanomeline with similar in vivo effects did not inhibit acetylcholinesterase or choline acetyltransferase and inhibited choline uptake only at concentrations much higher than those required to inhibit binding. These data indicate xanomeline is selective agonist for M1 over M2 and M3 receptors in vivo in rat.
Xanomeline (LY-246,708LumeronMemcor) is a muscarinic acetylcholine receptor agonist with reasonable selectivity for the M1 and M4 subtypes,[1][2][3][4] though it is also known to act as a M5 receptor antagonist.[5] It has been studied for the treatment of both Alzheimer’s disease and schizophrenia, particularly the cognitive and negative symptoms,[6] although gastrointestinal side effects led to a high drop-out rate in clinical trials.[7][8] Despite this, xanomeline has been shown to have reasonable efficacy for the treatment of schizophrenia symptoms, and one recent human study found robust improvements in verbal learning and short-term memoryassociated with xanomeline treatment.[9]
Image result for Xanomeline

Xanomeline oxalate

CAS No.:141064-23-5,

Molecular Weight, :371.45,

Molecular Formula, :C16H25N3O5S

5‐[4‐(hexyloxy)‐1,2,5‐thiadiazol‐3‐yl]‐1‐methyl‐1,2,3,6‐tetrahydropyridine; oxalic acid

SEE………..

Title: Xanomeline

CAS Registry Number: 131986-45-3

CAS Name: 3-[4-(Hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine

Molecular Formula: C14H23N3OS

Molecular Weight: 281.42

Percent Composition: C 59.75%, H 8.24%, N 14.93%, O 5.69%, S 11.39%

Literature References: Selective muscarinic M1-receptor agonist.

Prepn: P. Sauerberg, P. H. Olesen, EP384288 (1990 to Ferrosan); eidem,US5043345 (1991 to Novo Nordisk); eidemet al.,J. Med. Chem.35, 2274 (1992).

Prepn of crystalline tartrate: L. M. Osborne et al.,WO9429303 (1994 to Novo Nordisk).

Muscarinic receptor binding study: H. E. Shannon et al.,J. Pharmacol. Exp. Ther.269, 271 (1994). Pharmacology: F. P. Bymaster et al.,ibid. 282.

HPLC determn in plasma: C. L. Hamilton et al.,J. Chromatogr.613, 365 (1993).

Derivative Type: Oxalate

CAS Registry Number: 141064-23-5

Molecular Formula: C14H23N3OS.C2H2O4

Molecular Weight: 371.45

Percent Composition: C 51.74%, H 6.78%, N 11.31%, O 21.54%, S 8.63%

Properties: Crystals from acetone, mp 148°.

Melting point: mp 148°

Derivative Type: (+)-L-Hydrogen tartrate

CAS Registry Number: 152854-19-8

Additional Names: Xanomeline tartrate

Manufacturers’ Codes: LY-246708; NNC-11-0232

Trademarks: Lomeron (Lilly); Memcor (Lilly)

Molecular Formula: C14H23N3OS.C4H6O6

Molecular Weight: 431.50

Percent Composition: C 50.10%, H 6.77%, N 9.74%, O 25.95%, S 7.43%

Properties: Crystals from 2-propanol, mp 95.5°.

Melting point: mp 95.5°

Therap-Cat: Cholinergic; nootropic.

Keywords: Cholinergic; Nootropic.

SYNTHESIS WILL BE UPDATED

Image result for Xanomeline

Image result for Xanomeline

EP 0384288; US 5260311; US 5264444; US 5328925, US 5834495; WO 9429303, EP 0687265; JP 1996507298; WO 9420495
The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.

Figure

PAPER

Image result for Xanomeline nmr

http://www.mdpi.com/1420-3049/6/3/142/htm

Xanomeline (39) has emerged as one of the most potent unbridged arecoline derivatives. It has higher potency and efficacy for m1 and m4 than for m2, m3 and m5 receptor subtypes [73], binds to the m1receptor subtype uniquely tightly [74,75] and stimulates phosphoinositide hydrolysis in the brain. In cells containing human m1 receptors which are stably expressing amyloid precursor protein (APP), xanomeline (39) stimulates APP release with a potency 1000 greater than carbachol and reduces the secretion of Aβ by 46% [76] (cf 2.6 Central nervous system). In patients with Alzheimer’s disease, it halted cognitive decline and reduced behavioural symptoms such as hallucinations, delusions and vocal outbursts [77,78]. As might be expected there have been numerous attempts to prepare analogues with comparable potency and efficacy. Transplanting the thiadiazole ring of xanomeline to a range of bicyclic amines reduced selectivity [79,80] as did the use of pyrazine analogues (40) [81].

Paper

J Med Chem 1992,35(12),2274-83

see http://pubs.acs.org/doi/pdf/10.1021/jm00090a019

PAPER

Classics in Chemical Neuroscience: Xanomeline

 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
§ Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
ACS Chem. Neurosci.20178 (3), pp 435–443
DOI: 10.1021/acschemneuro.7b00001
Publication Date (Web): January 31, 2017
Copyright © 2017 American Chemical Society

Abstract

Abstract Image

Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer’s disease (AD) patients. Despite the compound’s promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound’s unique M1/M4-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M1 or M4. This Review will address xanomeline’s overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.

PAPER

References

  1. Jump up^ Farde L, Suhara T, Halldin C, et al. (1996). “PET study of the M1-agonists [11C]xanomeline and [11C]butylthio-TZTP in monkey and man”. Dementia (Basel, Switzerland)7 (4): 187–95. PMID 8835881.
  2. Jump up^ Jakubík J, Michal P, Machová E, Dolezal V (2008). “Importance and prospects for design of selective muscarinic agonists” (PDF). Physiological Research / Academia Scientiarum Bohemoslovaca. 57 Suppl 3: S39–47. PMID 18481916.
  3. Jump up^ Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA (January 2009). “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 Pharmacology603 (1-3): 147–9. PMID 19111716doi:10.1016/j.ejphar.2008.12.020.
  4. Jump up^ Heinrich JN, Butera JA, Carrick T, et al. (March 2009). “Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists”European Journal of Pharmacology605 (1-3): 53–6. PMID 19168056doi:10.1016/j.ejphar.2008.12.044.
  5. Jump up^ Grant MK, El-Fakahany EE (October 2005). “Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor”The Journal of Pharmacology and Experimental Therapeutics315 (1): 313–9. PMID 16002459doi:10.1124/jpet.105.090134.
  6. Jump up^ Lieberman JA, Javitch JA, Moore H (August 2008). “Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry”The American Journal of Psychiatry165 (8): 931–6. PMID 18676593doi:10.1176/appi.ajp.2008.08050769.
  7. Jump up^ Messer WS (2002). “The utility of muscarinic agonists in the treatment of Alzheimer’s disease”. Journal of Molecular Neuroscience : MN19 (1-2): 187–93. PMID 12212779doi:10.1007/s12031-002-0031-5.
  8. Jump up^ Mirza NR, Peters D, Sparks RG (2003). “Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists”. CNS Drug Reviews9 (2): 159–86. PMID 12847557doi:10.1111/j.1527-3458.2003.tb00247.x.
  9. Jump up^ Shekhar A, Potter WZ, Lightfoot J, et al. (August 2008). “Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia”The American Journal of Psychiatry165 (8): 1033–9. PMID 18593778doi:10.1176/appi.ajp.2008.06091591.
Xanomeline
Xanomeline.png
Clinical data
ATC code
  • None
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.208.938
Chemical and physical data
Formula C14H23N3OS
Molar mass 281.42 g/mol
3D model (JSmol)

///////XanomelineLY 246708, LumeronMemcor, ксаномелин كسانوميلين 诺美林 allosteric modulation, Alzheimer’s disease, antipsychotic,  muscarinic acetylcholine receptors, schizophrenia, 

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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