CLEARLY, I BELIEVE THERE IS SCIENTIFIC SUPPORT FOR ANAVEX’S DRUGS, WHICH ACT AS MUSCARINIC AND SIGMA 1 RECEPTOR AGONIST. SIGMA 1 RECEPTORS PLAY A ROLE ON MITOCHONDRIAL FUNCTIONS RELEVANT TO NEURODEGENERATIVE DISEASES. THIS POST IS AN ATTEMPT TO SIMPLIFY THE DISCUSSION ABOUT WHETHER ANAVEX IS LEADING US DOWN A RABBIT TRAIL, WHICH I BELIEVE IS NOT THE CASE. THEREFORE, THIS IS A SIMPLE AND STRAIGHT FOWARD RESPONSE TO REFUTE A COUPLE OF CRITICS ON THIS BOARD THAT I BELIEVE ARE DEAD WRONG IN THEIR PERSISTENT EFFORTS TO CASTIGATE THE ANAVEX CLINICAL TRIALS BEFORE THE TRIALS ARE CONCLUDED TO ESTABLISH WHETHER ANAVEX’S DRUGS ARE BENEFICIAL IN TREATING CNS DISEASES. THESE CRITICS SEEM TO DOOM ANAVEX TO FAILURE EVEN BEFORE THE COMPANY HAS A CHANCE TO PROVE OR DISPROVE WHETHER ITS DRUGS ARE USEFUL TO TREAT CNS DISEASES. I BELIEVE THAT ANAVEX IS A BONA FIDE PIONEER IN SEARCHING FOR A TREATMENT FOR CNS DISEASES WHERE ALL OTHERS BEFORE HAVE FAILED. THERE IS A BASIS FOR THE PATH PURSUED BY ANAVEX, AND EVEN THE HARSHEST SKEPTICS NEED TO AT LEAST GIVE ANAVEX A CHANCE TO PROVE OR DISPROVE WHETHER ITS DRUGS ARE BENEFICIAL TO TREAT CNS DISEASES, WHICH HERETOFORE HAVE NO EFFECTIVE TREATMENT. HOWEVER, I DOUBT THIS OR ANY POST WILL DISSUADE THESE CLOSED MINDED CRITICS. AT LEAST, THIS POST MAY HELP TO ENCOURAGE OTHERS TO DO THEIR OWN DD AND DECIDE FOR THEMSELVES RATHER THAN BE INFLUENCED BY ME OR ANYONE ELSE (INCLUDING THE SINGLE-MINDED CRITICS).
Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases
Tzu-Yu Weng, Shang-Yi Anne Tsai, and Tsung-Ping Su
Additional article information
Associated Data
Data Availability Statement All data in this review are already published and are available in public domains.
Abstract
The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.
Keywords: Sigma-1 receptor, Mitochondria, Mitochondrion-associated ER membrane (MAM), Neurodegenerative disorders
ANAVEX2-73 is a sigma-1 receptor agonist with muscarinic receptor activity... https://onlinelibrary.wiley.com/doi/full/10.1111/jch.13197 THE FOLLOWING IS FROM WIKIPEDIA AND INCLUDES REFERENCES: 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]
ANAVEX2-73
ANAVEX2-73.svg Legal status Legal status Investigational Identifiers IUPAC name 1-(2,2-Diphenyltetrahydro-3-furanyl)-N,N-dimethylmethanamine CAS Number 195615-83-9 ChemSpider 8057864 UNII 9T210MMZ3F Chemical and physical data Formula C19H23NO Molar mass 281.40 g·mol-1 3D model (JSmol) Interactive image SMILES O3C(c1ccccc1)(c2ccccc2)C(CN(C)C)CC3 InChI InChI=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 Key:BOTHKNZTGGXFEQ-UHFFFAOYSA-N Properties and usesEdit Edit
ANAVEX2-73 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.[clarification needed]Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks ß-secretase, which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme[clarification needed] is involved in the formation of Tau plaques, which are common in Alzheimer's disease.[clarification needed][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 Aß25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.[clarification needed] 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]
References Edit
^ a b c d e "Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma" (PDF). Journal of Psychopharmacology. Archived from the original(PDF) on 2015-11-12. Retrieved 2016-05-25. ^ a b c "ANAVEX 2-73 - AdisInsight". Adisinsight.springer.com. Retrieved 2016-05-25. ^ a b c Malviya, M; Kumar, YC; Asha, D; Chandra, JN; Subhash, MN; Rangappa, KS (2008). "Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models". Bioorg Med Chem. 16: 7095–7101. doi:10.1016/j.bmc.2008.06.053. ^ a b Leal, NS; Schreiner, B; Pinho, CM; Filadi, R; Wiehager, B; Karlström, H; Pizzo, P; Ankarcrona, M (2016). "Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid ß-peptide production". J Cell Mol Med. 20: 1686–1695. doi:10.1111/jcmm.12863. PMID 27203684. ^ Lahmy, V; Long, R; Morin, D; Villard, V; Maurice, T (2015-09-28). "Mitochondrial protection by the mixed muscarinic/s1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aß25-35 peptide-injected mice, a nontransgenic Alzheimer's disease model". Front Cell Neurosci. 8: 463. doi:10.3389/fncel.2014.00463. PMC 4299448. PMID 25653589. ^ Maurice, T (2015-09-28). "Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments". Behav. Brain Res. 296: 270–8. doi:10.1016/j.bbr.2015.09.020. PMID 26386305.
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