Siramesine fumarate | CAS#163630-79-3 | CAS#147817-50-3 | sigma receptor agonist

MedKoo Cat#: 529521 | Name: Siramesine fumarate

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Siramesine fumarate is a sigma receptor agonist potentially for the treatment of generalized anxiety disorder

Chemical Structure

Siramesine fumarate

CAS#163630-79-3 (fumarate)

Theoretical Analysis

MedKoo Cat#: 529521

Name: Siramesine fumarate

CAS#: 163630-79-3 (fumarate)

Chemical Formula: C34H35FN2O5

Exact Mass: 0.0000

Molecular Weight: 570.66

Elemental Analysis: C, 71.56; H, 6.18; F, 3.33; N, 4.91; O, 14.02

Price and Availability

Size	Price	Availability	Quantity
10mg	USD 275.00
25mg	USD 565.00

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Related CAS #

224177-60-0 (HCl) 147817-50-3 (free base) 163630-79-3 (fumarate)

Synonym

LU-28-179; LU-28179; LU 28 179

IUPAC/Chemical Name

1'-(4-(1-(4-fluorophenyl)-1H-indol-3-yl)butyl)-3H-spiro[isobenzofuran-1,4'-piperidine] fumarate

InChi Key

VONJQLKJOYOVBE-WLHGVMLRSA-N

InChi Code

InChI=1S/C30H31FN2O.C4H4O4/c31-25-12-14-26(15-13-25)33-21-23(27-9-2-4-11-29(27)33)7-5-6-18-32-19-16-30(17-20-32)28-10-3-1-8-24(28)22-34-30;5-3(6)1-2-4(7)8/h1-4,8-15,21H,5-7,16-20,22H2;1-2H,(H,5,6)(H,7,8)/b;2-1+

SMILES Code

FC1=CC=C(N2C=C(CCCCN3CCC4(CC3)OCC5=C4C=CC=C5)C6=C2C=CC=C6)C=C1.O=C(O)/C=C/C(O)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

To be determined

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Siramesine is a sigma receptor agonist, selective for the σ2 subtype In animal studies, siramesine produced anxiolytic and antidepressant effects. Siramesine has been shown to produce an enhanced antidepressant effect when co-administered with NMDA antagonists. It has also been used to study the σ2 activity of cocaine, and has been shown to produce anticancer properties both in vitro and in vivo.

In vitro activity:

Cell death in siramesine-treated cells is mitochondria-dependent and occurs independently of lysosomal membrane permeabilization. Siramesine induces rapid cell death in a number of cell lines. In HaCaT cells, cell death was accompanied by caspase activation, rapid loss of mitochondrial membrane potential (MMP), cytochrome c release, cardiolipin peroxidation and typical apoptotic morphology, whereas in U-87MG cells most apoptotic hallmarks were not notable, although MMP was rapidly lost. Reference: Cell Death Dis. 2013 Oct 3;4(10):e818. https://pubmed.ncbi.nlm.nih.gov/24091661/

In vivo activity:

Siramesine holds promise as a treatment for cutaneous mastocytoses and inflammatory skin diseases aggravated by dermal mast cells. Siramesine significantly reduced the total number of mast cells in both lesional and uninvolved psoriatic skin biopsies without affecting the gross morphology of the tissue. Siramesine reduced the density of IL-6- and IL-17-positive mast cells, and showed antiproliferative effects on epidermal keratinocytes with no apparent cytotoxic effect on keratinocytes or dermal fibroblasts. Reference: Br J Dermatol. 2017 Jul;177(1):179-187. https://pubmed.ncbi.nlm.nih.gov/28117878/

Preparing Stock Solutions

The following data is based on the product molecular weight 570.66 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Garcia EA, Bhatti I, Henson ES, Gibson SB. Prostate Cancer Cells Are Sensitive to Lysosomotropic Agent Siramesine through Generation Reactive Oxygen Species and in Combination with Tyrosine Kinase Inhibitors. Cancers (Basel). 2022 Nov 8;14(22):5478. doi: 10.3390/cancers14225478. PMID: 36428570; PMCID: PMC9688505. 2. Česen MH, Repnik U, Turk V, Turk B. Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Cell Death Dis. 2013 Oct 3;4(10):e818. doi: 10.1038/cddis.2013.361. PMID: 24091661; PMCID: PMC3824671. 3. Klawonn AM, Nilsson A, Rådberg CF, Lindström SH, Ericson M, Granseth B, Engblom D, Fritz M. The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum. Front Pharmacol. 2017 Oct 10;8:714. doi: 10.3389/fphar.2017.00714. PMID: 29066971; PMCID: PMC5641388. 4. Hagforsen E, Lampinen M, Paivandy A, Weström S, Velin H, Öberg S, Pejler G, Rollman O. Siramesine causes preferential apoptosis of mast cells in skin biopsies from psoriatic lesions. Br J Dermatol. 2017 Jul;177(1):179-187. doi: 10.1111/bjd.15336. Epub 2017 May 15. PMID: 28117878.

In vitro protocol:

In vivo protocol:

1. Klawonn AM, Nilsson A, Rådberg CF, Lindström SH, Ericson M, Granseth B, Engblom D, Fritz M. The Sigma-2 Receptor Selective Agonist Siramesine (Lu 28-179) Decreases Cocaine-Reinforced Pavlovian Learning and Alters Glutamatergic and Dopaminergic Input to the Striatum. Front Pharmacol. 2017 Oct 10;8:714. doi: 10.3389/fphar.2017.00714. PMID: 29066971; PMCID: PMC5641388. 2. Hagforsen E, Lampinen M, Paivandy A, Weström S, Velin H, Öberg S, Pejler G, Rollman O. Siramesine causes preferential apoptosis of mast cells in skin biopsies from psoriatic lesions. Br J Dermatol. 2017 Jul;177(1):179-187. doi: 10.1111/bjd.15336. Epub 2017 May 15. PMID: 28117878.

1: Česen MH, Repnik U, Turk V, Turk B. Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes. Cell Death Dis. 2013 Oct 3;4:e818. doi: 10.1038/cddis.2013.361. PubMed PMID: 24091661; PubMed Central PMCID: PMC3824671. 2: Spirkoski J, Melo FR, Grujic M, Calounova G, Lundequist A, Wernersson S, Pejler G. Mast cell apoptosis induced by siramesine, a sigma-2 receptor agonist. Biochem Pharmacol. 2012 Dec 15;84(12):1671-80. doi: 10.1016/j.bcp.2012.09.028. PubMed PMID: 23058984. 3: Ma S, Henson ES, Chen Y, Gibson SB. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016 Jul 21;7:e2307. doi: 10.1038/cddis.2016.208. PubMed PMID: 27441659; PubMed Central PMCID: PMC4973350. 4: Ostenfeld MS, Høyer-Hansen M, Bastholm L, Fehrenbacher N, Olsen OD, Groth-Pedersen L, Puustinen P, Kirkegaard-Sørensen T, Nylandsted J, Farkas T, Jäättelä M. Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy. 2008 May;4(4):487-99. PubMed PMID: 18305408. 5: Jonhede S, Petersen A, Zetterberg M, Karlsson JO. Acute effects of the sigma-2 receptor agonist siramesine on lysosomal and extra-lysosomal proteolytic systems in lens epithelial cells. Mol Vis. 2010 May 8;16:819-27. PubMed PMID: 20461150; PubMed Central PMCID: PMC2866574. 6: Hagforsen E, Lampinen M, Paivandy A, Weström S, Velin H, Öberg S, Pejler G, Rollman O. Siramesine causes preferential apoptosis of mast cells in skin biopsies from psoriatic lesions. Br J Dermatol. 2017 Jan 24. doi: 10.1111/bjd.15336. [Epub ahead of print] PubMed PMID: 28117878. 7: Ostenfeld MS, Fehrenbacher N, Høyer-Hansen M, Thomsen C, Farkas T, Jäättelä M. Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res. 2005 Oct 1;65(19):8975-83. PubMed PMID: 16204071. 8: Zimmermann A, Tian F, Lopez de Diego H, Ringkjøbing Elema M, Rantanen J, Müllertz A, Hovgaard L. Influence of the solid form of siramesine hydrochloride on its behavior in aqueous environments. Pharm Res. 2009 Apr;26(4):846-54. doi: 10.1007/s11095-008-9783-0. PubMed PMID: 19005740. 9: Parry MJ, Alakoskela JM, Khandelia H, Kumar SA, Jäättelä M, Mahalka AK, Kinnunen PK. High-affinity small molecule-phospholipid complex formation: binding of siramesine to phosphatidic acid. J Am Chem Soc. 2008 Oct 1;130(39):12953-60. doi: 10.1021/ja800516w. PubMed PMID: 18767848. 10: Zimmermann A, Tian F, de Diego HL, Frydenvang K, Rantanen J, Elema MR, Hovgaard L. Structural characterisation and dehydration behaviour of siramesine hydrochloride. J Pharm Sci. 2009 Oct;98(10):3596-607. doi: 10.1002/jps.21679. PubMed PMID: 19156865. 11: Groth-Pedersen L, Ostenfeld MS, Høyer-Hansen M, Nylandsted J, Jäättelä M. Vincristine induces dramatic lysosomal changes and sensitizes cancer cells to lysosome-destabilizing siramesine. Cancer Res. 2007 Mar 1;67(5):2217-25. PubMed PMID: 17332352. 12: Søby KK, Mikkelsen JD, Meier E, Thomsen C. Lu 28-179 labels a sigma(2)-site in rat and human brain. Neuropharmacology. 2002 Jul;43(1):95-100. PubMed PMID: 12213263. 13: Zimmermann A, Millqvist-Fureby A, Elema MR, Hansen T, Müllertz A, Hovgaard L. Adsorption of pharmaceutical excipients onto microcrystals of siramesine hydrochloride: effects on physicochemical properties. Eur J Pharm Biopharm. 2009 Jan;71(1):109-16. doi: 10.1016/j.ejpb.2008.06.014. PubMed PMID: 18619536. 14: Nielsen AB, Buur A, Larsen C. Bioreversible quaternary N-acyloxymethyl derivatives of the poorly soluble tertiary amine Lu 28-179--synthesis, pharmaceutical chemical characterization and bioavailability studies in dogs. Eur J Pharm Sci. 2005 Dec;26(5):421-8. PubMed PMID: 16150581. 15: Sánchez C, Papp M. The selective sigma2 ligand Lu 28-179 has an antidepressant-like profile in the rat chronic mild stress model of depression. Behav Pharmacol. 2000 Apr;11(2):117-24. PubMed PMID: 10877116. 16: Heading C. Siramesine H Lundbeck. Curr Opin Investig Drugs. 2001 Feb;2(2):266-70. Review. PubMed PMID: 11816842. 17: Sánchez C, Arnt J, Costall B, Kelly ME, Meier E, Naylor RJ, Perregaard J. The selective sigma2-ligand Lu 28-179 has potent anxiolytic-like effects in rodents. J Pharmacol Exp Ther. 1997 Dec;283(3):1323-32. Erratum in: J Pharmacol Exp Ther 1998 May;285(2):929. PubMed PMID: 9400007. 18: Hagforsen E, Paivandy A, Lampinen M, Weström S, Calounova G, Melo FR, Rollman O, Pejler G. Ablation of human skin mast cells in situ by lysosomotropic agents. Exp Dermatol. 2015 Jul;24(7):516-21. doi: 10.1111/exd.12699. PubMed PMID: 25808581. 19: Petersen NH, Olsen OD, Groth-Pedersen L, Ellegaard AM, Bilgin M, Redmer S, Ostenfeld MS, Ulanet D, Dovmark TH, Lønborg A, Vindeløv SD, Hanahan D, Arenz C, Ejsing CS, Kirkegaard T, Rohde M, Nylandsted J, Jäättelä M. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell. 2013 Sep 9;24(3):379-93. doi: 10.1016/j.ccr.2013.08.003. PubMed PMID: 24029234. 20: Skuza G, Rogóz Z. The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats. J Physiol Pharmacol. 2006 Jun;57(2):217-29. PubMed PMID: 16845227.