Sunday, December 30, 2018 9:56:57 AM
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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603014/
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.
https://en.m.wikipedia.org/wiki/ANAVEX2-73
Recent AVXL News
- May 13, 2024 Deadline: Contact The Gross Law Firm to Join Class Action Suit Against AVXL • PR Newswire (US) • 04/26/2024 09:45:00 AM
- Contact The Gross Law Firm by May 13, 2024 Deadline to Join Class Action Against Anavex Life Sciences Corporation(AVXL) • PR Newswire (US) • 04/19/2024 09:45:00 AM
- The Gross Law Firm Reminds Shareholders of a Lead Plaintiff Deadline of May 13, 2024 in Anavex Life Sciences Lawsuit - AVXL • PR Newswire (US) • 04/16/2024 09:45:00 AM
- Class Action Filed Against Anavex Life Sciences Corporation (AVXL) - May 13, 2024 Deadline to Join - Contact The Gross Law Firm • PR Newswire (US) • 04/12/2024 09:45:00 AM
- Anavex Life Sciences to Present at the Noble Capital Markets Virtual Healthcare Equity Conference • GlobeNewswire Inc. • 04/11/2024 11:30:00 AM
- Class Action Filed Against Anavex Life Sciences Corporation (AVXL) - May 13, 2024 Deadline to Join - Contact The Gross Law Firm • PR Newswire (US) • 04/09/2024 09:45:00 AM
- Anavex Life Sciences Corporation Class Action: The Gross Law Firm Reminds Anavex Life Sciences Investors of the Pending Class Action Lawsuit with a Lead Plaintiff Deadline of May 13, 2024 - AVXL • PR Newswire (US) • 04/05/2024 09:45:00 AM
- Shareholders that lost money on Anavex Life Sciences Corporation(AVXL) should contact The Gross Law Firm about pending Class Action - AVXL • PR Newswire (US) • 04/02/2024 09:45:00 AM
- Lost Money on Anavex Life Sciences Corporation(AVXL)? Join Class Action Suit Seeking Recovery - Contact The Gross Law Firm • PR Newswire (US) • 03/29/2024 09:45:00 AM
- Investors who lost money on Anavex Life Sciences Corporation(AVXL) should contact The Gross Law Firm about pending Class Action - AVXL • PR Newswire (US) • 03/26/2024 09:45:00 AM
- Anavex Life Sciences to Present at the 23rd Annual Needham Virtual Healthcare Conference • GlobeNewswire Inc. • 03/25/2024 11:30:00 AM
- The Gross Law Firm Notifies Anavex Life Sciences Corporation Investors of a Class Action Lawsuit and Upcoming Deadline • PR Newswire (US) • 03/22/2024 09:45:00 AM
- Anavex Life Sciences Initiates Placebo-Controlled U.S. Phase 2 Clinical Trial of ANAVEX®3-71 in Schizophrenia • GlobeNewswire Inc. • 03/18/2024 11:30:00 AM
- Anavex Life Sciences to Present at the 44th Annual TD Cowen Health Care Conference • GlobeNewswire Inc. • 02/26/2024 12:30:00 PM
- Form 4 - Statement of changes in beneficial ownership of securities • Edgar (US Regulatory) • 02/23/2024 11:05:18 AM
- Form 4 - Statement of changes in beneficial ownership of securities • Edgar (US Regulatory) • 02/23/2024 11:04:32 AM
- Form 4 - Statement of changes in beneficial ownership of securities • Edgar (US Regulatory) • 02/23/2024 11:04:31 AM
- Form 4 - Statement of changes in beneficial ownership of securities • Edgar (US Regulatory) • 02/23/2024 11:03:48 AM
- Form 4 - Statement of changes in beneficial ownership of securities • Edgar (US Regulatory) • 02/23/2024 11:03:06 AM
- Form 10-Q - Quarterly report [Sections 13 or 15(d)] • Edgar (US Regulatory) • 02/07/2024 09:31:07 PM
- Anavex Life Sciences Reports Fiscal 2024 First Quarter Financial Results and Provides Business Update • GlobeNewswire Inc. • 02/07/2024 12:30:00 PM
- Anavex Life Sciences to Announce Fiscal 2024 First Quarter Financial Results on Wednesday, February 7th, 2024 • GlobeNewswire Inc. • 02/01/2024 12:30:00 PM
- Form SC 13G/A - Statement of acquisition of beneficial ownership by individuals: [Amend] • Edgar (US Regulatory) • 01/25/2024 10:01:34 PM
- Anavex Life Sciences Reports Publication of ANAVEX®3-71 in Clinical Journal Confirming Pharmacokinetic Dose Proportionality of ANAVEX®3-71 in Humans • GlobeNewswire Inc. • 01/24/2024 12:30:00 PM
- Anavex Life Sciences Announces U.S. Phase 2 Clinical Trial of ANAVEX®3-71 in Schizophrenia • GlobeNewswire Inc. • 01/16/2024 12:30:00 PM
Bantec Reports an Over 50 Percent Increase in Sales and Profits in Q1 2024 from Q1 2023 • BANT • Apr 25, 2024 10:00 AM
Cannabix's Breath Logix Alcohol Device Delivers Positive Impact to Private Monitoring Agency in Montana, USA • BLO • Apr 25, 2024 8:52 AM
Kona Gold Beverages, Inc. Announces Name Change to NuVibe, Inc. and Initiation of Ticker Symbol Application Process • KGKG • Apr 25, 2024 8:30 AM
Axis Technologies Group and Carbonis Forge Ahead with New Digital Carbon Credit Technology • AXTG • Apr 24, 2024 3:00 AM
North Bay Resources Announces Successful Equipment Test at Bishop Gold Mill, Inyo County, California • NBRI • Apr 23, 2024 9:41 AM
Epazz, Inc.: CryObo, Inc. solar Bitcoin operations will issue tokens • EPAZ • Apr 23, 2024 9:20 AM