Indatraline

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Indatraline
Clinical data
ATC code
  • none
Identifiers
  • (1S,3R)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine
CAS Number
PubChem CID
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H15Cl2N
Molar mass292.2072 g·mol−1

Indatraline (Lu 19-005) is a nonselective monoamine reuptake 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.[1] Research has also suggested that indatraline can be used to block the action of methamphetamine.[2]

SAR

Compare Indatraline with tametraline since they are directly homologous.

There are some differences though.

Computational overlay should make it possible to see that there is at least a relationship between the pharmacophores in indatraline and various phenyltropanes.

If a very bulky alkyl group is positioned on the amine, it is possible to make completely inactive prodrugs, that only become bioactive upon dealkylation in vivo.[3]

Cis 3,4-Dichloro Indamines B = Binding, U = Uptake (nM)
R1 R2 DAT DA SERT 5-HT NET NE
Me H 290 500 38 4.0 600 130
Me Me 63 550 2.4 5.5 150 86
Et H 140 1000 4.7 19 no data 170
Et Me 660 530 13 72 2400 4400
Pr H 280 620 500 1300 540 630
Pr Me 1200 1000 200 810 2000 540
Pri H 450 1400 130 300 3500 1500
Pri Me 680 960 73 1800 650 1800
But H 650 1500 1700 >10μM 1100 1800
But Me 2800 >10μM >10μM no data 2200 >10μM
Bn H 1100 5300 2100 >10μM 4800 >10μM
Bn Me >10μM no data 300 700 >10μM >10μM
Trans 3,4-Dichloro Indamines B = Binding, U = Uptake (nM)
R1 R2 DAT DA SERT 5-HT NET NE
Me H 27 23 5.0 4.8 22 15
Me Me 19 200 0.33 65 95 34
Et H 8.1 61 2.0 13 48 28
Et Me 39 270 16 24 250 150
Pr H 220 53 130 480 55 130
Pr Me 250 340 91 190 400 640
Pri H 32 51 93 240 110 75
Pri Me 180 190 44 1500 260 420
But H 130 370 740 3100 150 310
But Me 890 2700 4700 >10μM 440 1000
Bn H 80 130 380 >10μM 460 2600
Bn Me 120 550 180 3700 2800 1600
Trans 3,4-Dichloro Indamines B = Binding, U = Uptake (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

Chemistry

2 main routes have been reported.

The first route shown is the original one reported by Bøgesø and co-workers.[4]

the other had been adapted to scale-up:[5]

File:Indatralinesynth2.png

Although a new method of making indatraline was recently published,[6] there is obviously more than one way of making this compound.

See for example: 6525206

Unfortunately for the indananone 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.

References

  1. ^ Negus SS, Brandt MR, Mello NK. "Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys." J Pharmacol Exp Ther (1999) 291(1):60-9. PMID 10490887
  2. ^ Rothman, BR, et al. "Neurochemical Neutralization of Methamphetamine With High-Affinity Nonselective Inhibitors of Biogenic Amine Transporters: A Pharmacological Strategy for Treating Stimulant Abuse." Synapse (2000) 35:222-227. PMID 10657029
  3. ^ Gardner EL, Liu X, Paredes W, Giordano A, Spector J, Lepore M, Wu KM, Froimowitz M. A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: effects in laboratory rat models relating to addiction. Neuropharmacology. 2006 Oct;51(5):993-1003. PMID 16901516
  4. ^ Bøgesø KP, Christensen AV, Hyttel J, Liljefors T. 3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake. J Med Chem. 1985 Dec;28(12):1817-28. PMID 2999402
  5. ^ Froimowitz M, Wu KM, Moussa A, Haidar RM, Jurayj J, George C, Gardner EL. Slow-onset, long-duration 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse. J Med Chem. 2000 Dec 28;43(26):4981-92. PMID 11150168
  6. ^ Silva LF Jr, Siqueira FA, Pedrozo EC, Vieira FY, Doriguetto AC. Iodine(III)-promoted ring contraction of 1,2-dihydronaphthalenes: a diastereoselective total synthesis of (+/-)-indatraline. Org Lett. 2007 Apr 12;9(8):1433-6. PMID 17371034
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