- Acetylcholinesterase (AChE): Tacrine inhibits AChE with an IC50 of 31 nM (snake venom AChE). The inhibition kinetics show a mixed-type inhibition. Ki (inhibition constant) is 13 nM. KI (dissociation constant of AChE-ASCh-tacrine complex) is 20 nM, and γKm is 0.086 mM. Km for acetylthiocholine hydrolysis is 0.0537 mM. [1]
- Butyrylcholinesterase (BChE): Tacrine inhibits human serum BChE with an IC50 of 25.6 nM. Ki is 12 nM. KI is 10 nM, and γKm is 0.147 mM. Km for acetylthiocholine hydrolysis is 0.0299 mM. [1]
- N-methyl-D-aspartate receptors (NMDARs): Tacrine acts as an open-channel blocker. IC50 for inhibiting NMDAR responses in cultured hippocampal neurons is approximately 190 μM (at -60 mV). It displaces [³H]TCP (PCP site ligand) with an IC50 of 26 μM in rat brain homogenate, with a Ki of 15 μM. [2]

- Cholinesterase Inhibition Kinetics: Tacrine inhibits snake venom AChE and human serum BChE in a concentration-dependent manner (12.5-37.5 nM). Lineweaver-Burk plots show a mixed-type inhibition (increased Km, decreased Vmax). For AChE, Vmaxapp increased from 177.99 to 431.03 μmol/min per mg and KIapp increased from 17 to 23 nM with increasing substrate concentration (0.05-1.0 mM). For BChE, Vmaxapp increased from 0.173 to 0.396 μmol/min per mg and KIapp from 9 to 16.2 nM. [1]
- NMDAR Inhibition (Electrophysiology): In cultured hippocampal neurons, tacrine (1 mM) substantially inhibits NMDAR currents at negative membrane potentials, sensing 56% of the transmembrane electrostatic field. Tacrine (30-300 μM) also inhibits NMDAR currents in cultured cerebellar granule cells. Bis(7)-tacrine, a dimeric derivative, inhibits NMDARs with an IC50 of 0.66 μM at -50 mV. [2]
- Neuroprotection Against Oxidative Stress: In ARPE-19 human retinal pigment epithelial cells, tacrine (at unspecified concentrations) inhibits H2O2-induced apoptosis. H2O2 (1000 μM, 2h) induces AChE expression and PARP cleavage, indicating apoptosis. AChE expression is induced during apoptosis. [3]
- Receptor Binding: Tacrine displaces [³H]dizocilpine (MK-801) binding at the PCP site on NMDARs in rat cerebral cortex, indicating interaction with this site. [2]

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In a concentration-dependent manner, tacrine (12.5-37.5 nM) inhibits both human blood butyrylcholinesterase and venom acetylcholinesterase [1]. With an IC50 of roughly 500 μM, tacrine lessens the neurotoxicity brought on by NMDAR activation in mouse cortical neuron cultures [2]. With an IC50 of roughly 190 μM at -60 mV, tacrine suppresses the NMDAR response in a concentration-dependent manner [2].

- Retinal Protection in AChE Knockout Mice: In AChE-deficient mice (AChE⁺/⁻), intraperitoneal injection of tacrine (0.1, 0.2, 0.4 mg/mL, daily for 7 days) does not significantly improve retinal morphology or structure compared to PBS controls (P > 0.05). The retina of AChE⁺/⁻ mice is thinner than wild-type, and the structure becomes more disorganized with age (2 mo vs. 4 mo). Tacrine treatment shows a reduction of histologic features compared to wild-type, but the protective effect does not significantly change with increasing concentration. [3]
- Cognitive Enhancement (Rodent Models): Tacrine (1 mg/kg, i.p.) combined with D-cycloserine (3 mg/kg) improves spatial navigation deficits in aged rats in the Morris water maze when administered 30 min before daily testing. Tacrine alone reverses scopolamine-induced amnesia in passive avoidance and water Y-maze tests. Intraseptal tacrine infusion enhances radial maze performance in rats. High doses of tacrine (20-40 μmol/kg) disrupt retention of learning in mice. [2]

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In mice aged 17 and 30, tacrine (20–40 μmol/kg; subcutaneous injection) reduces their ability to retain passive avoidance learning, but low-dose tacrine treatment (5 μmol/kg; subcutaneous injection) enhances their capacity to retain learning in 17-day-old mice [2]. Although tacrine (0.1–0.4 mg/mL; intraperitoneal injection for 7 days) can suppress AChE expression, its protective effects on mouse retinal morphology and function are not appreciably enhanced [3].

- Cholinesterase Activity Assay (Ellman method): Hydrolysis rates were measured at various acetylthiocholine (ASCh) concentrations (0.05-1 mM) in 1 mL assay solutions with 62 mM phosphate buffer (pH 7.5) and 0.2 mM DTNB at 25°C. Human serum (40 μL, 700 μg protein) or snake venom (4 μg protein) was pre-incubated for 10 min at 37°C. 0.06 mM ethopropazine was used in the AChE assay to inhibit BChE. The hydrolysis was monitored by the formation of the thiolate dianion of DTNB at 412 nm for 2-3 min using a spectrophotometer. [1]
- Kinetic Parameter Determination: Kinetic parameters were determined using Lineweaver-Burk double reciprocal plots (1/V vs. 1/S) and Cornish-Bowden plots (S/V vs. [I]). IC50 was determined by plotting percentage residual activity vs. tacrine concentration. Ki, KI, and γKm values were calculated using Dixon and Lineweaver-Burk plots. [1]
- NMDAR Binding Assays: [³H]TCP binding assays were performed in rat brain homogenate to determine displacement by tacrine. Saturation curves were calculated to determine Ki. [2]

- ARPE-19 Cell Culture and H₂O₂ Treatment: ARPE-19 cells were treated with H₂O₂ (0, 250, 500, 1000, 2000 μmol/L) to induce apoptosis. Western blot analysis was performed to detect AChE and cleaved PARP expression at 2h. [3]
- Double Immunofluorescence (AChE/TUNEL): ARPE-19 cells were fixed, permeabilized, and incubated with anti-AChE primary antibody followed by rhodamine-conjugated secondary antibody. TUNEL reaction was performed using a TUNEL reaction mixture for 1h. Cells were observed under a fluorescence microscope to confirm AChE expression in apoptotic cells. [3]
- Cultured Neuron Electrophysiology (Patch Clamp): Whole-cell and single-channel patch-clamp recordings were performed on cultured hippocampal neurons or cerebellar granule cells. NMDAR currents were elicited by application of NMDA (with glycine). Tacrine was co-applied to assess inhibition. Currents were recorded at various membrane potentials to determine voltage-dependency. [2]
- NSC-34 Cell Viability Assay: Tacrine (at unspecified concentrations) was tested for its effect on NMDAR-mediated excitotoxicity, though data is not detailed in the provided excerpts. [2]

- AChE Knockout Mouse Study: Heterozygous AChE knockout mice (AChE⁺/⁻) and wild-type S129 mice (2 mo and 4 mo old) were used. Tacrine (0.1, 0.2, 0.4 mg/mL) or donepezil was administered intraperitoneally once daily for 7 days. PBS was used as control. Mice were sacrificed after 30 days by in vitro cardiac perfusion, and retinal samples were collected. H&E staining was performed to observe retinal morphology. AChE deficiency was confirmed by PCR genotyping and Western blot. [3]
- Rat Morris Water Maze Study: Aged rats were trained in a Morris water maze. Tacrine (1 mg/kg, i.p.) and/or D-cycloserine (3 or 10 mg/kg) was administered 30 min before daily testing. Latency to find the hidden platform was measured. [2]

Serum concentrations are noted to be low in the context of retinal protection studies. [2][3]

- Hepatotoxicity: Tacrine is known to cause significant hepatotoxicity, which led to its withdrawal from the market. This is mentioned in review sections. [2]
- In Vivo Toxicity (Retinal Study): In the AChE knockout mouse study, no experimental mice died during the 7-day intraperitoneal injection period with tacrine at doses of 0.1, 0.2, and 0.4 mg/mL. [3]
- In Vitro Toxicity (Cell Viability): High concentrations of tacrine (e.g., 20-40 μmol/kg in vivo) disrupt learning and memory in mice, indicating potential neurotoxicity at high doses. [2]

[1]. Inhibition of two different cholinesterases by tacrine. Chem Biol Interact. 2006 Aug 25; 162(2):165-71.

[2]. The pharmacology of tacrine at N-methyl-d-aspartate receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr 3;75: 54-62.

[3]. The protective role of tacrine and donepezil in the retina of acetylcholinesterase knockout mice. Int J Ophthalmol. 2015 Oct 18; 8(5): 884-90.

- Chemical Properties: Tacrine is a white crystalline water-soluble powder with a planar configuration and a pKa of 9.85. At neutral pH, it is fully ionized, with the positive charge delocalized over mesomeric structures. [2]
- Mechanism of Action (Complex): Beyond AChE inhibition, tacrine blocks potassium channels, inhibits sodium channel inactivation, inhibits monoamine oxidase (MAO-A and MAO-B), inhibits histamine N-methyltransferase, and modulates adenosine receptors. Its precognitive effect is also linked to M1 muscarinic receptor activation, which inhibits Ca²⁺-activated potassium channels (SK channels), delaying membrane repolarization and prolonging NMDAR activation, thereby facilitating long-term potentiation (LTP). [2]
- Clinical History: Tacrine was the first AChE inhibitor approved for AD treatment (1993 in the USA) but was withdrawn in 2013 due to hepatotoxicity and the availability of safer alternatives. [2]
- Neuroprotective Mechanism: Tacrine protects against glutamate-induced neurotoxicity and oxidative stress (H₂O₂) by reducing apoptosis. This effect may involve nicotinic ACh receptor activation, as it is blocked by mecamylamine. [2][3]

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1,2,3,4-Tetrahydro-9-aminoacridine hydrochloride monohydrate is a yellow needle-like crystal (precipitated by concentrated hydrochloric acid); or a white powder. A 1.5% solution has a pH of 4.5-6. It tastes bitter. (NTP, 1992)
Tacrine hydrochloride is the hydrochloride form of tacrine, an aminoacridine derivative with cognitive stimulating effects. Although its mechanism of action is not fully elucidated, tacrine hydrochloride may reversibly bind to cholinesterase, acetylcholinesterase, and butyrylcholinesterase, thereby reducing the breakdown of acetylcholine, prolonging synaptic interactions, and increasing the release of acetylcholine. Furthermore, the drug inhibits monoamine oxidase (MAO) and may inhibit the reuptake of catecholamines and serotonin. Finally, a novel mechanism of action studied in animal models suggests that tacrine attenuates the production of interleukin-1β in the hippocampus and blood, thereby producing central and peripheral anti-inflammatory effects, which may play a role in Alzheimer's disease. Tacrine is a cholinesterase inhibitor that can cross the blood-brain barrier. It has been used to antagonize the effects of muscle relaxants, as a respiratory stimulant, and to treat Alzheimer's disease and other central nervous system disorders. See also: Tacrine (containing the active ingredient).

C13H15CLN2

234.73

270.113

C, 66.52; H, 6.44; Cl, 15.10; N, 11.93

1684-40-8

1684-40-8 (hydrochloride); 321-64-2; Tacrine hydrochloride (hydrate);206658-92-6

2723754

White to light yellow solid powder

409.4ºC at 760mmHg

280-284 °C(lit.)

230.5ºC

6.49E-07mmHg at 25°C

4.079

2

2

0

16

229

0

C1CCC2=NC3=CC=CC=C3C(=C2C1)N.Cl

ZUFVXZVXEJHHBN-UHFFFAOYSA-N

InChI=1S/C13H14N2.ClH/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13;/h1,3,5,7H,2,4,6,8H2,(H2,14,15);1H

1,2,3,4-tetrahydroacridin-9-amine;hydrochloride

NSC-72108; NSC 72108; NSC72108 Tacrine hydrochloride; 1684-40-8; Tacrine HCl; Hydroaminacrine; Tenakrin; Hydroaminacrine

2934.99.9001

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 (e.g. under nitrogen), avoid exposure to moisture.

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

H2O : ~33.33 mg/mL (~142.00 mM)

Solubility in Formulation 1: 16.67 mg/mL (71.02 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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