Indatraline

Indatraline

File:Indatraline.png
Systematic (IUPAC) name
(1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine
Clinical data
Routes of administration	Oral
Legal status
Legal status	Uncontrolled
Identifiers
CAS Number	86939-10-8
ATC code	none
PubChem	CID 126280
Chemical data
Formula	C16H15Cl2N
Molar mass	292.2072 g/mol[[]]

Indatraline (Lu 19-005) is a non-selective monoamine transporter inhibitor that has been shown to block the reuptake of dopamine, norepinephrine, and serotonin with effects similar to those of cocaine. 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 and MDMA.

Compare Indatraline with tametraline since they are directly homologous. There are some differences though. Superposition 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 prodrugs 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 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]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 between the two enantiomers of N-methyl-indatraline is not as high as was reported in the case of 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. 300px (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.

800px

the other had been adapted to scale-up:

800px

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

See also

• Sertraline
• Tametraline