Tetrabenazine

Absorption

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients

Toxicity

Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg

Description

Tetrabenazine (58-46-8) is a potent inhibitor of the vesicular monoamine transporter (VMAT), IC50=3.2 nM1,2?with selectivity for VMAT2 over VMAT13. Promotes late stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3-positive endocrine precursors.4

Chemical properties

White to Off-White Solid

Originator

Nitoman,Roche,UK,1960

The Uses of Tetrabenazine

Tetrabenazine has been used for dopamine uptake assays in mouse brain cells¹. Tetrabenazine has also been used for non-specific binding assays in postnuclear supernatants derived from PC-12 and CV-1 cells².

The Uses of Tetrabenazine

Dopamine depleting agent. An antidyskinetic; antipsychotic.

Indications

Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia

Background

A drug formerly used as an antipsychotic but now used primarily in the symptomatic treatment of various hyperkinetic disorders. It is a monoamine depletor and used as symptomatic treatment of chorea associated with Huntington's disease. FDA approved on August 15, 2008.

What are the applications of Application

Tetrabenazine is a potent inhibitor of vesicular monoamine uptake

Definition

ChEBI: A benzoquinolizine that is 1,2,3,4,4a,9,10,10a-octahydrophenanthrene in which the carbon at position 10a is replaced by a nitrogen and which is substituted by an isobutyl group at position 2, an oxo group at position 3, and methoxy groups at positions 6 an 7.

Manufacturing Process

280 grams of 1-carbethoxymethyl-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline, 150 grams of mono-isobutylmalonic acid dimethyl ester and 35 grams of paraformaldehyde were refluxed for 24 hours in 1,000 ml of methanol. Upon cooling, 1-carbethoxymethyl-2-(2,2-dicarbomethoxy-4- methyl-n-pentyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline crystallized; MP after recrystallization from methanol, 94° to 96°C. The latter was subjected to Dieckmann cyclization, hydrolysis and decarboxylation in the following manner.
28 grams of sodium was dissolved in 650 ml of absolute ethanol, the solution was concentrated to dryness, and the residue was mixed with 3,600 ml of toluene and 451 grams of the intermediate prepared above. The mixture was heated, and the methanol formed by condensation was distilled off until the boiling point of toluene was reached. The mixture was thereupon refluxed for 2 hours, and then it was concentrated to dryness. The residue was dissolved in 5,200 ml of 3 N hydrochloric acid and heated for 14 hours at 120°C, thereby effecting hydrolysis and decarboxylation. The mixture was cooled, washed with diethyl ether, decolorized with carbon, made alkaline and taken up in diethyl ether. The process yields 2-oxo-3-isobutyl-9,10-dimethoxy- 1,2,3,4,6,7-hexahydro-11b-benzo[a]quinolizine; MP after recrystallization from diisopropyl ether, 126° to 128°C.

Therapeutic Function

Tranquilizer

General Description

A cell permeable benzoquinolizine based compound that acts as a monoamine-depleting agent by blocking the activity vesicular monoamine transporter 2. Promotes late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3 (Ngn3)-positive endocrine precursors without increasing their proliferation. Increases the number of insulin expressing cells in a dose dependent manner (EC₅₀ = 220 nM) and this effect is significantly enhanced when cells are simultaneously treated with dibutyryl cAMP. Embryonic stem cells treated with TBZ and/or dibutyryl cAMP and then grafted into kidney capsule of AKITA mice reduce hyperglycemia, improve fasting blood glucose levels, and show an increase in plasma C-peptide levels.

Biological Activity

Potent inhibitor of vesicular monoamine uptake; depletes stores of dopamine, serotonin and noradrenalin. Binds with high affinity (IC 50 = 3.2 nM) to vesicular monoamine transporter (VMAT) in chromaffin granule membranes and displays higher affinity for VMAT2 than VMAT1. Also reported to block dopamine receptors. Causes behavioral depression; inhibits locomotor activity and produces hypothermia upon systemic administration in rats and mice.

Biochem/physiol Actions

Primary TargetVMAT2

Pharmacokinetics

Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

Metabolism

Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine.

storage

+4°C

Purification Methods

Crystallise it from MeOH. The hydrochloride has m 208-210o, and the oxime has m 158o (from EtOH). [Beilstein 21 III/IV 6488.]