Indatraline hydrochloride (Lu 19-005) is an antidepressive agent and non-selective

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

inhibitor that blocks the

reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, and

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

with similar efficacy to

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

. This compound may be used to treat cocaine addictions as its effects have a slower onset and a longer duration than those of cocaine. Indatraline has been shown to block the action of

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

and

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

in laboratory experiments.

Methylation

Indatraline is ''N''-alkylated at the amino group, making it possible to slow the onset of action, so that it is not until ''N''-demethylation occurs that the molecules become active. ''N''-methylindatraline has a longer duration than indatraline because norindatraline is inactive, whereas demethylating ''N''-methylindatraline does not terminate the actions of the parent compound. Effects of ''N''-dimethylindatraline start about 20–30 minutes after administration; it takes a longer time for this chemical to absorb into the body than cocaine.

Synthesis

Two main routes have been reported. The first route was reported by Bøgesø and co-workers. Indatralinesynth

The other has been adapted to scale-up: Indatra

Another method involves the contraction of a dihydronaphthalene (6–6 fused system) to form the 6–5 indane skeleton. Routes based on 1-indanone-type intermediates are not as simple as a direct reduction of an

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...

oxime In organic chemistry, an oxime is an organic compound belonging to the imines, with the general Chemical formula, formula , where R is an organic Side chain, side-chain and R' may be hydrogen, forming an aldoxime, or another organic functional g ...

. The undesirable cis diastereomers are formed instead of the desirable trans isomers. This adds an extra step to the synthetic route. First, the ketones are reduced to mostly cis alcohols. Second, the cis alcohols are converted to the corresponding mesylates, conserving stereochemistry. Third, the mesylates can then be reacted, e.g. with, ''N''-methylbenzylamine, causing a

Walden inversion Walden inversion is the inversion of a stereogenic center in a chiral molecule in a chemical reaction. Since a molecule can form two enantiomers around a stereogenic center, the Walden inversion converts the configuration of the molecule from ...

(SN2). Finally, the removal of the benzyl affords the product as a racemic mixture.

References

{{Monoamine reuptake inhibitors Substance dependence 1-Aminoindanes Chloroarenes Serotonin–norepinephrine–dopamine reuptake inhibitors Stimulants

Methylation

Synthesis

See also

References