indatraline
{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| verifiedrevid = 437144053
| IUPAC_name = (1R,3S)-3-(3,4-dichlorophenyl)-N-methyl-2,3-dihydro-1H-inden-1-amine
| image = trans-Indatraline Structure.svg
| image_class = skin-invert-image
| tradename =
| pregnancy_category =
| legal_status = Uncontrolled
| routes_of_administration = By mouth
| bioavailability =
| metabolism =
| elimination_half-life =
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 86939-10-8
| ATC_prefix = none
| ATC_suffix =
| PubChem = 126280
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 16736639
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4U40Y96J1Z
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| synonyms = Lu 19-005
| ChEMBL = 146332
| C = 16
| H = 15
| Cl = 2
| N = 1
| smiles = Clc1ccc(cc1Cl)[C@@H]3C[C@H](NC)c2ccccc23
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SVFXPTLYMIXFRX-BBRMVZONSA-N
}}
Indatraline hydrochloride (Lu 19-005) is an antidepressive agent and non-selective monoamine transporter inhibitor that blocks the reuptake of dopamine, norepinephrine, and serotonin with similar efficacy to cocaine.{{cite journal | vauthors = Cho YS, Yen CN, Shim JS, Kang DH, Kang SW, Liu JO, Kwon HJ | title = Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 34655 | date = October 2016 | pmid = 27694974 | pmc = 5046148 | doi = 10.1038/srep34655 | bibcode = 2016NatSR...634655C }} This compound may be used to treat cocaine addictions as its effects have a slower onset and a longer duration than those of cocaine.{{cite journal | vauthors = Negus SS, Brandt MR, Mello NK | title = Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 291 | issue = 1 | pages = 60–69 | date = October 1999 | pmid = 10490887 }} Indatraline has been shown to block the action of methamphetamine and MDMA in laboratory experiments.{{cite journal | vauthors = Rothman RB, Partilla JS, Baumann MH, Dersch CM, Carroll FI, Rice KC | title = Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse | journal = Synapse | volume = 35 | issue = 3 | pages = 222–227 | date = March 2000 | pmid = 10657029 | doi = 10.1002/(SICI)1098-2396(20000301)35:3<222::AID-SYN7>3.0.CO;2-K | s2cid = 16190813 | url = https://zenodo.org/record/1235504 }}
Methylation
Indatraline is N-alkylated at the amino group, making it 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 longer duration than indatraline because norindatraline is inactive, whereas demethylating N-methylindatraline does not terminate the actions of the parent compound.{{Citation needed|date=March 2025}}
Effects of N-dimethylindatraline start about 20–30 minutes after administration; it takes a longer time for this chemical to absorb into the body than cocaine.{{cite journal |vauthors=Gardner EL, Liu X, Paredes W, Giordano A, Spector J, Lepore M, Wu KM, Froimowitz M |date=October 2006 |title=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 |journal=Neuropharmacology |volume=51 |issue=5 |pages=993–1003 |doi=10.1016/j.neuropharm.2006.06.009 |pmid=16901516 |s2cid=20465584}}
Synthesis
Two main routes have been reported. The first route was reported by Bøgesø and co-workers.{{cite journal | vauthors = Bøgesø KP, Christensen AV, Hyttel J, Liljefors T | title = 3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake | journal = Journal of Medicinal Chemistry | volume = 28 | issue = 12 | pages = 1817–28 | date = December 1985 | pmid = 2999402 | doi = 10.1021/jm00150a012 }}
Another method involves the contraction of a dihydronaphthalene (6–6 fused system) to form the 6–5 indane skeleton.{{cite journal | vauthors = Silva LF, Siqueira FA, Pedrozo EC, Vieira FY, Doriguetto AC | title = Iodine(III)-promoted ring contraction of 1,2-dihydronaphthalenes: a diastereoselective total synthesis of (±)-indatraline | journal = Organic Letters | volume = 9 | issue = 8 | pages = 1433–6 | date = April 2007 | pmid = 17371034 | doi = 10.1021/ol070027o }}
Routes based on 1-indanone-type intermediates are not as simple as a direct reduction of an imine or oxime. 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 mostly cis alcohols. Second, the cis alcohols are converted to the corresponding mesylates, conserving stereochemistry. Third, the mesylates can then be reacted, e.g. with, N-methylbenzylamine, causing a Walden inversion (SN2). Finally, the removal of the benzyl affords the product as a racemic mixture.{{Citation needed|date=March 2025}}
See also
References
{{Reflist}}
{{Stimulants}}
{{Monoamine reuptake inhibitors}}
Category:Serotonin–norepinephrine–dopamine reuptake inhibitors