Chemical Properties
White to Off-White Solid
Uses
Dopamine depleting agent. An antidyskinetic; antipsychotic.
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.
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.
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
Originator
Nitoman,Roche,UK,1960
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.
Biochem/physiol Actions
Primary TargetVMAT2
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.]
References
1) Scherman?et al. (1983),?Characterization of the monoamine carrier of chromaffin granule membrane by binding of [2-3H]dihydrotetrabenazine; Proc. Natl. Acad. Sci. USA,?80?584
2) Peter?et al. (1996),?Chimeric vesicular monoamine transporters identify structural domains that influence substrate affinity and sensitivity to tetrabenazine; J. Biol. Chem.,?271?2979
3) Schafer?et al. (2013),?Localization and expression of VMAT2 across mammalian species: a translational guide for it’s visualization and targeting in health and disease; Adv. Pharmacol.,?68?319
4) Sakano?et al. (2014),?VMAT2 identified as a regulator of late-stage β-cell differentiation; Nat. Chem. Biol.,?10?141
