Indatraline

Indatraline (Lu 19-005) is a non-selective monoamine transporter inhibitor shown to block the reuptake of dopamine, norepinephrine, and serotonin, with effects similar to those of cocaine. 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.[1] LU 19-005 has been shown to block the action of methamphetamine and MDMA in laboratory experiments.[2]

Indatraline
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
IUPAC name
  • (1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H15Cl2N
Molar mass292.20 g·mol−1
3D model (JSmol)
SMILES
  • Clc1ccc(cc1Cl)[C@@H]3C[C@H](NC)c2ccccc23
InChI
  • InChI=1S/C16H15Cl2N/c1-19-16-9-13(11-4-2-3-5-12(11)16)10-6-7-14(17)15(18)8-10/h2-8,13,16,19H,9H2,1H3/t13-,16-/m0/s1 Y
  • Key:SVFXPTLYMIXFRX-BBRMVZONSA-N Y
  (verify)

Superposition should make it possible to see there is at least a fundamental relationship between the pharmacophore of indatraline and various phenyltropanes.[3]

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.[3]

Synthesis

Two 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]

Another method involves contraction of a dihydronaphthalene (6–6 fused system) to form the 6–5 indane skeleton.[6]

Routes based on 1-indanone types of intermediates are not as simple as a direct reduction of an imine or oxime. 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, effecting a Walden inversion (SN2). Finally, removal of the benzyl affords the product as a racemic mixture.

See also

References
  1. Negus SS, Brandt MR, Mello NK (October 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): 60–9. PMID 10490887.
  2. Rothman RB, Partilla JS, Baumann MH, Dersch CM, Carroll FI, Rice KC (March 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. S2CID 16190813.
  3. Gardner EL, Liu X, Paredes W, Giordano A, Spector J, Lepore M, et al. (October 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. S2CID 20465584.
  4. Bøgesø KP, Christensen AV, Hyttel J, Liljefors T (December 1985). "3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake". Journal of Medicinal Chemistry. 28 (12): 1817–28. doi:10.1021/jm00150a012. PMID 2999402.
  5. Froimowitz M, Wu KM, Moussa A, Haidar RM, Jurayj J, George C, Gardner EL (December 2000). "Slow-onset, long-duration 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse". Journal of Medicinal Chemistry. 43 (26): 4981–92. doi:10.1021/jm000201d. PMID 11150168.
  6. Silva LF, Siqueira FA, Pedrozo EC, Vieira FY, Doriguetto AC (April 2007). "Iodine(III)-promoted ring contraction of 1,2-dihydronaphthalenes: a diastereoselective total synthesis of (±)-indatraline". Organic Letters. 9 (8): 1433–6. doi:10.1021/ol070027o. PMID 17371034.
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