Latrepirdine (Dimebolin) HCl 97657-92-6_5-HT Receptor_GPCR & G Protein_Signaling Pathways_Products

Latrepirdine HCl (Dimebon; Dimebolin; Dimeboline; Preparation 84), the hydrochloride salt of Latrepirdine, is an orally bioactive, neuroactive and non-selective antihistamine drug with the potential to be used for Alzheimer's disease and Huntington's disease. In addition, it is an antagonist of several other targets, such as GluR and 5-HT receptors, which are used in antihistamine medications. It has been demonstrated that latrepirdine prevents the death of brain cells in animal models of Huntington's and Alzheimer's diseases. According to research, it might also improve cognition in healthy people. Russia and other nations have employed latrepirdine in clinical settings; however, a Phase III clinical trial for the treatment of Alzheimer's disease was unable to demonstrate any benefit.

Physicochemical Properties

Molecular Formula

C21H27CL2N3

Molecular Weight

392.37

Exact Mass

391.158

Elemental Analysis

C, 64.28; H, 6.94; Cl, 18.07; N, 10.71

CAS #

97657-92-6

Related CAS #

3613-73-8; 97657-92-6 (HCl)

PubChem CID

23729232

Appearance

White to khaki solid powder

LogP

5.425

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

425

Defined Atom Stereocenter Count

SMILES

Cl.N1C(C)=CC=C(CCN2C3CCN(CC=3C3C2=CC=C(C)C=3)C)C=1

InChi Key

GTWLIQOLGOZTLF-UHFFFAOYSA-N

InChi Code

InChI=1S/C21H25N3.2ClH/c1-15-4-7-20-18(12-15)19-14-23(3)10-9-21(19)24(20)11-8-17-6-5-16(2)22-13-17;;/h4-7,12-13H,8-11,14H2,1-3H3;2*1H

Chemical Name

2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrido[4,3-b]indole;dihydrochloride

Synonyms

Dimebon; Dimeboline; Dimebolin; Latrepirdine; Preparation 84

HS Tariff Code

2934.99.9001

Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets

Histaminergic receptor; Serotonergic receptor; Amyloid-β (Aβ); α-adrenergic receptor

ln Vitro

In vitro activity: Latrepirdine has been shown to have a number of characteristics that may be useful in the treatment of neurodegenerative diseases: (1) shielding cultured cells from the cytotoxicity of amyloid-β (Aβ) peptide; (2) maintaining calcium homeostasis and mitochondrial function; (3) controlling the release of Aβ from hippocampal neurons in living mice brains, isolated intact nerve terminals, and cultured cells; and (4) stimulating neurogenesis in the murine hippocampus. Latrepirdine treatment of cultured mammalian cells increases Atg5- and mTOR-dependent autophagy. Through the mTOR-signaling pathway, latrepirdine dose-dependently regulates Atg5-dependent autophagic activity. HeLa cells with LC3 fused stable expression are treated with EGFP (eGFP-LC3) either in the presence or absence of 50 μM Latrepirdine for 3 or 6 hours. The number of eGFP-LC3 punctae is significantly increased after receiving latrepirdine for three or six hours, suggesting that latrepirdine promotes the formation of autophagosomes. The effects of acute drug treatment on the regulation of autophagy are then investigated using mouse N2a neuroblastoma cells treated for 3 or 6 hours in the presence (vehicle) or absence (5 nM, 500 nM, or 50 μM) of latrepirdine. After treating N2a cells with 500 nM or 50 μM latrepirdine for three or six hours, there is a notable and dose-dependent rise in LC3-II levels. The N2a cells treated with 50 μM Latrepirdine for 3 hours show a significant decrease in p-mTOR and p-S6K, while the levels of total mTOR and p70S6K stay relatively constant[1].

ln Vivo

Latrepirdine treatment of TgCRND8 transgenic mice is linked to better learning behavior and decreased accumulation of α-synuclein and Aβ42. Ninety-day-old male TgCRND8 mice or their wild-type littermates (nTg) are given injections intraperitoneally (i.p.) 31 times a day in either 0.9% saline (vehicle) or 3.5 mg/kg latrepirdine. Using a paradigm that has been widely accepted for assessing learning and memory deficits in APP transgenic mice, mice are tested for cued and contextual fear conditioning at the end of treatment. There is only a statistically significant (p=0.01) improvement in cued memory in TgCRND8 mice treated with latrepirdine as opposed to vehicle. Additionally, there is a slight, non-significant trend (p=0.099) showing that mice treated with Latrepirdine had better contextual memory than mice treated with a vehicle[1].

Cell Assay

The following are kept in "growth medium" (high glucose Dulbecco's modified Eagle's medium supplemented with 10% FBS and 100 units/mL Penicillin/Streptomycin) at 37°C, 5% CO₂: N2a cells, stable human cervical carcinoma (HeLa) cells expressing EGFP-LC3, and mouse embryonic fibroblasts (MEFs) derived from wildtype mice or ATG5^-/- mice. N2a cells that have been transfected with APPK670N and M671L are kept in growth medium that has been enhanced with 0.2 mg/mL G418. After a 1-inch wash with ice-cold PBS (pH 7.4), the cells are cultured in growth medium or latrepirdine (5 nM, 500 nM, or 50 μM). After treatment for three, six, or twenty-four hours, cells are collected and centrifuged at 14,000 RPM for fifteen minutes at 4°C in lysis buffer (50 mM Tris-HCl, 150 mM NaCl, 1 mM Pepstatin, 1 mM PMSF, 1% Triton X-100, EDTA-free mini-complete protease inhibitor cocktail tablet). In time-course studies, cells are rinsed twice with ice-cold PBS (pH 7.4) and then cultured in serum-free DMEM supplemented with 50 μg/mL CHX or 50 μg/mL Cycloheximide (CHX)+50 μg/mL Chloroquine (CQ) for the specified duration. Samples for baseline (T₀) are taken right before treatment[1].

Animal Protocol

3.5 mg/kg; i.p.

Mice: MMale TgCRND8 mice, aged 53–55 days (N = 25), are randomized to receive either latrepirdine (n = 13 TgCRND8) or vehicle (n = 12 TgCRND8) as their treatment. The animals are given intraperitoneal injections of 0.9% saline (vehicle) or 3.5 mg/kg latrepirdine for 21 consecutive days. Two treatment groups are randomly assigned to 90-day-old male TgCRND8 mice (N=28) or their wild-type littermates (N=56). The treatment groups are either latrepirdine (n=13 TgCRND8; n=21 nTg) or vehicle (n=15 TgCRND8; n=25 nTg). After therapy, the animals are transcardially perfused with ice-cold PBS (pH 7.4) and sacrificed. Male TgCRND8 mice, aged 90 days (n = 5 per genotype) or 120 days (n = 6 per genotype), along with their non-transgenic littermates, are sacrificed and given an ice-cold PBS solution (pH 7.4) intracardially. For histological analysis, one hemisphere of each mouse is post-fixed in 4% paraformaldehyde in PBS (pH 7.4), while the other hemisphere is dissected and snap-frozen for biochemical analysis.

References

[1]. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model. Mol Psychiatry. 2013 Aug;18(8):889-97.

Solubility Data

Solubility (In Vitro)

DMSO: 6.4~24 mg/mL (16.3~61.2 mM)

Water: <1 mg/mL

Ethanol: ~13 mg/mL (~33.1 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 0.5 mg/mL (1.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 0.5 mg/mL (1.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

Solubility in Formulation 3: ≥ 0.5 mg/mL (1.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

Solubility in Formulation 4: 100 mg/mL (254.86 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5486 mL	12.7431 mL	25.4861 mL
	5 mM	0.5097 mL	2.5486 mL	5.0972 mL
	10 mM	0.2549 mL	1.2743 mL	2.5486 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

Latrepirdine (Dimebolin) HCl 97657-92-6

CAS No.: 97657-92-6

Physicochemical Properties

Biological Activity

Solubility Data