Indatraline is a non-selective

Binding selectivity

Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...

 monoamine transporter

Monoamine transporter

Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...

 inhibitor that has been shown to block the reuptake

Reuptake

Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....

 of dopamine

Dopamine

Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

, norepinephrine

Norepinephrine

Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

, and serotonin

Serotonin

Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 with effects similar to those of cocaine

Cocaine

Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

. However, the effects have been shown to have slower onset and longer duration than cocaine, suggesting that the compound may, along with similar compounds, be used for treatment of cocaine addiction. Apparently, Lu 19-005 can be used to block the action of methamphetamine

Methamphetamine

Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...

 and MDMA.

Compare Indatraline with tametraline

Tametraline

Tametraline is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline .Sertraline has been called "3,4-dichloro tametraline"...

 since they are directly homologous. There are some differences though. Superposition

Superposition principle

In physics and systems theory, the superposition principle , also known as superposition property, states that, for all linear systems, the net response at a given place and time caused by two or more stimuli is the sum of the responses which would have been caused by each stimulus individually...

 should make it possible to see that there is at least a relationship between the pharmacophore of indatraline and various phenyltropanes. More recently, additional work has been done also:

Trans

If indatraline is N-alkylated it is possible to slow the onset of action, if the choice of alkyl group is sufficiently bulky, so that it is not until N-demethylation occurs that the molecules become really active. N-methyl indatraline has a much longer duration than indatraline, because norindatraline is inactive whereas demethylating N-methyl-indatraline does not terminate the actions of the parent compound. Most drug addiction programs are of the opinion that a "slow onset, long duration" DRI is less likely to be abused (c.f. Volkow and others). The N-methyl products are clearly not just inactive prodrug

Prodrug

A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...

s though.

Measurement of ambulation was recording in 10-minute bins. Whereas for cocaine, LMA was already apparent at 10 min, at least 20 minutes were needed before the NMe₂ analogs even started to increase locomotor activity. Very high doses actually (over the hill) meant less ambulation. The reason for this was increased stereotypy

Stereotypy

A stereotypy is a repetitive or ritualistic movement, posture, or utterance, found in people with mental retardation, autism spectrum disorders, tardive dyskinesia and stereotypic movement disorder. Stereotypies may be simple movements such as body rocking, or complex, such as self-caressing,...

 if you overbake it. It is apparent from the table that larger N-groups result in increased DAT selectivity relative to the SERT and NET. Although it is not necessary to enter into the details, the authors actually wanted a SNDRI.

Racemic

N-Demethyl analogs situated on the right-side of the arrow, assuming that this is the way they are metabolized in vivo.

[¹²⁵I

Iodine-125

Iodine-125 is a radioisotope of iodine which has uses in biological assays, nuclear medicine imaging and in radiation therapy as brachytherapy to treat prostate cancer and brain tumors. It is the second longest-lived radioisotope of iodine, after iodine-129.Its half-life is around 59 days and it...

]RTI-55 used as the binding ligand at all 3 transporters.

Racemic (trans) 3',4'-Dichloro Indamines. Ki and IC50 (nM)
Stereo	R1	R2	DAT	DA	SERT	5-HT	NET	NE
Rac	Me	Me	19 → 27	200 → 23	0.33 → 5.0	65 → 4.8	95 → 22	34 → 15
Rac	Et	Me	39 → 8.1	270 → 61	16 → 2.0	24 → 13	250 → 48	150 → 28
Rac	Pr	Me	250 → 220	340 → 53	91 → 130	190 → 480	400 → 55	640 → 130
Rac	Pri	Me	180 → 32	190 → 51	44 → 93	1500 → 240	260 → 110	420 → 75
Rac	But	Me	890 → 130	2700 → 370	4700 → 740	>10μM → 3100	440 → 150	1000 → 310
Rac	Bn	Me	120 → 80	550 → 380	180 → >10μM	3700 → >10μM	2800 → 460	1600 → 2600

Single Enantiomers

Trans 3',4'-Dichloro Indamines. Ki and IC50 (nM)
Stereo	R1	R2	DAT	DA	SERT	5-HT	NET	NE
(±)-trans	Me	Me	19	200	0.33	65	95	34
(+)-trans	Me	Me	8.7	120	0.06	6.3	52	21
(–)-trans	Me	Me	38	650	3.6	130	130	130

Interestingly, the eudysmic ratio

Eudysmic ratio

The Eudysmic ratio is a common term in pharmacology, chemistry, and molecular biology. The eudysmic ratio describes the difference in pharmacologic activity between the two enantiomers of a drug....

 between the two enantiomers of N-methyl-indatraline is not as high as was reported in the case of tametraline

Tametraline

Tametraline is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline .Sertraline has been called "3,4-dichloro tametraline"...

. The toxicity of the R,S isomer is less than for the S,R isomer.

Iodination

This was actually done for radiological purposes, although the compound was tested anyway.

(Rac) DAT: 310, DA: 290. SERT: 17, 5-HT: 3700. NET: 1400, NE: 3200.

The idea is a method to gain increased DA(T) selectivity relative to the other transporters.

Cis

Cis 3',4'-Dichloro Indamines. Ki and IC50 (nM)
R1	R2	DAT	DA	SERT	5-HT	NET	NE
Me	Me	63 → 290	550 → 500	2.4 → 38	5.5 → 4.0	150 → 600	86 → 130
Et	Me	660 → 140	530 → 1000	13 → 4.7	72 → 19	2400 → ?	4400 → 170
Pr	Me	1200 → 280	1000 → 620	200 → 500	810 → 1300	2000 → 540	540 → 630
Pri	Me	680 → 450	960 → 1400	73 → 130	1800 → 300	650 → 3500	1800 → 1500
But	Me	2800 → 650	>10μM → 1500	>10μM → 1700	? → >10μM	2200 → 1100	>10μM → 1800
Bn	Me	>10μM → 1100	? → 5300	300 → 2100	700 → >10μM	>10μM → 4800	>10μM → >10μM

Chemistry

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



the other had been adapted to scale-up:



Although a new method of making indatraline was recently published, there is obviously more than one way of making this compound.

See for example: 6525206

Unfortunately for the indanone intermediates a method is not available for direct reduction of the imine

Imine

An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...

 or oxime

Oxime

An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...

. It is reported that the wrong diastereomers are formed (cis) whereas the trans isomers are the ones that are needed. This frustrates the synthesis since an extra step has to be inserted. First the ketones are reduced to get mostly cis alcohols, which are then converted to the corresponding mesylates conserving stereochemistry. These can then be reacted with e.g. N-methylbenzylamine, effecting a Walden inversion

Walden inversion

Walden inversion is the inversion of a chiral center in a molecule in a chemical reaction. Since a molecule can form two enantiomers around a chiral center, the Walden inversion converts the configuration of the molecule from one enantiomeric form to the other. For example, in a SN2 reaction,...

(SN2). Final removal of the benzyl affords product, although it is racemic.