Indatraline (Lu 19-005) is a non- selective

monoamine transporter Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible for ...

inhibitor shown to block 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 transm ...

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

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

, and

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

, with effects similar to those of

cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

. The effects have been shown to have a slower onset and longer duration than cocaine, suggesting that the compound may, along with similar compounds, be used for the treatment of cocaine addiction. LU 19-005 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 and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...

and

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in Tablet (pharmacy), tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for Recreational dru ...

in laboratory experiments. Superposition should make it possible to see there is at least a fundamental relationship between the

pharmacophore 300px, An example of a pharmacophore model. A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. IUPAC defines a pharmacophore to be "an ensemble o ...

of indatraline and various

phenyltropanes Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, the ...

Methylation

If indatraline is ''N''-alkylated at the amino group, it is 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 much 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, making it less likely to be abused than cocaine.

Synthesis

Two main routes have been reported. The first route shown is the original one reported by Bøgesø and co-workers. Indatralinesynth

the other had 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 types of 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 bo ...

oxime In organic chemistry, an oxime is a organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R’ may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted ...

. It is reported that 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 get mostly cis alcohols. Second, the cis alcohols are converted to the corresponding mesylates conserving stereochemistry. Third, the mesylates can then be reacted with e.g. ''N''-methylbenzylamine, affecting 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