| 词条 | ANAVEX2-73 |
| 释义 |
}}{{Infobox drug | drug_name = | INN = | type = | IUPAC_name = 1-(2,2-Diphenyltetrahydro-3-furanyl)-N,N-dimethylmethanamine | image = ANAVEX2-73.svg | alt = | caption = | pronounce = | tradename = | Drugs.com = | MedlinePlus = | pregnancy_AU = | pregnancy_AU_comment = | pregnancy_US = | pregnancy_category= | routes_of_administration = | legal_AU = | legal_AU_comment = | legal_BR = | legal_BR_comment = | legal_CA = | legal_DE = | legal_NZ = | legal_UK = | legal_US = | legal_UN = | legal_status = Investigational | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion = | CAS_number = 195615-83-9 | class = | ATCvet = | ATC_prefix = | ATC_suffix = | PubChem = | ChemSpiderID = 8057864 | DrugBank = | UNII = 9T210MMZ3F | C=19|H=23|N=1|O=1 | smiles = O3C(c1ccccc1)(c2ccccc2)C(CN(C)C)CC3 | StdInChI=1S/C19H23NO/c1-20(2)15-18-13-14-21-19(18,16-9-5-3-6-10-16)17-11-7-4-8-12-17/h3-12,18H,13-15H2,1-2H3 | StdInChIKey=BOTHKNZTGGXFEQ-UHFFFAOYSA-N }}ANAVEX2-73 is an experimental drug is in Phase II trials for Alzheimer's disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson's disease, Rett syndrome, stroke.[1][2] ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist.[1] ANAVEX2-73 may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is the active metabolite of ANAVEX 1-41, which is similar to ANAVEX2-73 but it is not as selective for sigma receptor.[2] Properties and usesANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound.[2] ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment.[1] M1 receptor agonists are known to reverse the amnesia caused by scopolamine.[3] Scopolamine is used in the treatment of Parkinson's disease and motion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach.[3] This is via competitive inhibition of muscarinic receptors.[3] Muscarinic receptors are involved in the formation of both short term and long term memories.[1] Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta and target GSK-3B.{{Clarify|date=September 2017}} Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks β-secretase, which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme{{Clarify|date=September 2017}} is involved in the formation of Tau plaques, which are common in Alzheimer's disease.{{Clarify|date=September 2017}}[4] Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.[4] Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits.[1] The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.{{clarify|date=September 2017}} ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. ANAVEX2-73 also exhibits anti-apoptotic and anti-oxidant activity. This is due in part because sigma-1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB.[5] Results from Marice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or the memantine, a NMDA receptor antagonist.[6]References1. ^1 2 3 4 {{cite journal|url=http://anavex.com/files/Anti-amnesic%20and%20neuroprotective%20potentials%20of%20ANAVEX2-73.pdf |format=PDF |title=Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma |journal=Journal of Psychopharmacology |accessdate=2016-05-25 |deadurl=yes |archiveurl=https://web.archive.org/web/20151112120256/http://anavex.com/files/Anti-amnesic%20and%20neuroprotective%20potentials%20of%20ANAVEX2-73.pdf |archivedate=2015-11-12 }} {{Acetylcholine receptor modulators}}{{Sigma receptor modulators}}2. ^1 2 {{cite web|url=http://adisinsight.springer.com/drugs/800033840 |title=ANAVEX 2-73 - AdisInsight |website=Adisinsight.springer.com |date= |accessdate=2016-05-25}} 3. ^1 2 {{cite journal | last1 = Malviya | first1 = M | last2 = Kumar | first2 = YC | last3 = Asha | first3 = D | last4 = Chandra | first4 = JN | last5 = Subhash | first5 = MN | last6 = Rangappa | first6 = KS | year = 2008 | title = Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models | url = | journal = Bioorg Med Chem | volume = 16 | issue = | pages = 7095–7101 | doi=10.1016/j.bmc.2008.06.053}} 4. ^1 {{cite journal | last1 = Leal | first1 = NS | last2 = Schreiner | first2 = B | last3 = Pinho | first3 = CM | last4 = Filadi | first4 = R | last5 = Wiehager | first5 = B | last6 = Karlström | first6 = H | last7 = Pizzo | first7 = P | last8 = Ankarcrona | first8 = M | year = 2016 | title = Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production | url = | journal = J Cell Mol Med | volume = 20| issue = | pages = 1686–1695| doi = 10.1111/jcmm.12863 | pmid = 27203684 }} 5. ^{{Cite journal|author= |title= Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer's disease model|date=2015-09-28 |pmid=25653589 |doi=10.3389/fncel.2014.00463 |pmc=4299448 |volume=8 |pages=463 | last1 = Lahmy | first1 = V | last2 = Long | first2 = R | last3 = Morin | first3 = D | last4 = Villard | first4 = V | last5 = Maurice | first5 = T | journal=Front Cell Neurosci}} 6. ^{{Cite journal|author= |title= Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments|date=2015-09-28 |pmid=26386305 |doi=10.1016/j.bbr.2015.09.020 |volume=296 |pages=270–8 | last1 = Maurice | first1 = T |journal=Behav. Brain Res.}} 3 : Muscarinic antagonists|Sigma agonists|Prodrugs |
| 随便看 |
|
开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。