Indatraline

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Indatraline
Indatraline.png
Systematic (IUPAC) name
(1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine
Clinical data
  • Uncontrolled
Oral
Identifiers
86939-10-8 YesY
None
PubChem CID 126280
ChemSpider 16736639 YesY
UNII 4U40Y96J1Z YesY
ChEMBL CHEMBL146332 YesY
Chemical data
Formula C16H15Cl2N
292.2072 g/mol
 YesY (what is this?)  (verify)

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.[1] Apparently, Lu 19-005 can be used to block the action of methamphetamine and MDMA.[2]

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.[3]

Trans[edit]

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.[3] 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 recorded in 10-minute bins. Whereas for cocaine, locomotor activity (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 meant less ambulation. The reason for this was increased stereotypy. 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.[citation needed]

Racemic[edit]

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[edit]

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

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.

Cis[edit]

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[edit]

Two main routes have been reported. The first route shown is the original one reported by Bøgesø and co-workers.[4]

Indatralinesynth.png

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

Indatra.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 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[edit]

References[edit]

  1. ^ Negus, S. S.; Brandt, M. R.; Mello, N. K. (1999). "Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics 291 (1): 60–69. PMID 10490887.  edit
  2. ^ Rothman, R. B.; Partilla, J. S.; Baumann, M. H.; Dersch, C. M.; Carroll, F. I.; Rice, K. C. (2000). "Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse". Synapse 35 (3): 222–7. doi:10.1002/(SICI)1098-2396(20000301)35:3<222::AID-SYN7>3.0.CO;2-K. PMID 10657029.  edit
  3. ^ a b Gardner, E.; Liu, X.; Paredes, W.; Giordano, A.; Spector, J.; Lepore, M.; Wu, K.; Froimowitz, M. (2006). "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 51 (5): 993–1003. doi:10.1016/j.neuropharm.2006.06.009. PMID 16901516.  edit
  4. ^ Bøgesø, K. P.; Christensen, A. V.; Hyttel, J.; Liljefors, T. (1985). "3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake". Journal of Medicinal Chemistry 28 (12): 1817–1828. doi:10.1021/jm00150a012. PMID 2999402.  edit
  5. ^ Froimowitz, M.; Wu, K. M.; Moussa, A.; Haidar, R. M.; Jurayj, J.; George, C.; Gardner, E. L. (2000). "Slow-onset, long-duration 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse". Journal of Medical Chemistry 43 (26): 4981–4992. doi:10.1021/jm000201d. PMID 11150168.  edit
  6. ^ Silva Lf, J.; Siqueira, F.; Pedrozo, E.; Vieira, F.; Doriguetto, A. (2007). "Iodine(III)-promoted ring contraction of 1,2-dihydronaphthalenes: a diastereoselective total synthesis of (+/-)-indatraline". Organic Letters 9 (8): 1433–1436. doi:10.1021/ol070027o. PMID 17371034.  edit