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{{Short description|Chemical compound}}
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⚫
'''Indatraline hydrochloride''' ('''Lu 19-005''') is an [[Antidepressant|antidepressive agent]] and [[Binding selectivity|non-selective]] [[monoamine transporter]] inhibitor that blocks the [[reuptake]] of [[dopamine]], [[norepinephrine]], and [[serotonin]] with similar efficacy to [[cocaine]].<ref>{{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 }}</ref> This compound may be used to treat [[Cocaine dependence|cocaine addictions]] as its effects have a slower onset and a longer duration than those of cocaine.<ref>{{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 }}</ref> Lu 19-005 has been shown to block the action of [[methamphetamine]] and [[MDMA]] in laboratory experiments.<ref>{{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 }}</ref>


⚫
==Methylation==
{{Tone|date=March 2021}}
⚫
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.


⚫
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.<ref name="Gardner">{{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}}</ref>
⚫
'''Indatraline''' ('''Lu 19-005''') is a non-[[binding selectivity|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.<ref>{{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 = 60–9 | date = October 1999 | pmid = 10490887 }}</ref> Apparently, Lu 19-005 can be used to block the action of [[methamphetamine]] and [[MDMA]].<ref>{{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 = 222–7 | date = March 2000 | pmid = 10657029 | doi = 10.1002/(SICI)1098-2396(20000301)35:3<222::AID-SYN7>3.0.CO;2-K | url = https://zenodo.org/record/1235504 }}</ref>

⚫
[[Superposition principle|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.<ref name=Gardner>{{cite journal | vauthors = Gardner EL, Liu X, Paredes W, Giordano A, Spector J, Lepore M, Wu KM, Froimowitz M | display-authors = 6 | 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 | date = October 2006 | pmid = 16901516 | doi = 10.1016/j.neuropharm.2006.06.009 }}</ref>

⚫
==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.<ref name=Gardner/>


==Synthesis==
==Synthesis==
Two main routes have been reported. The first route shown is the original one reported by Bøgesø and co-workers.<ref>{{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 }}</ref>
Two main routes have been reported. The first route was reported by Bøgesø and co-workers.<ref>{{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 }}</ref>


[[File:Indatralinesynth.png|800px]]
[[File:Indatralinesynth.png|800px]]


the other had been adapted to scale-up:<ref>{{cite journal | vauthors = Froimowitz M, Wu KM, Moussa A, Haidar RM, Jurayj J, George C, Gardner EL | title = Slow-onset, long-duration 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 26 | pages = 4981–92 | date = December 2000 | pmid = 11150168 | doi = 10.1021/jm000201d }}</ref>
The other has been adapted to scale-up:<ref>{{cite journal | vauthors = Froimowitz M, Wu KM, Moussa A, Haidar RM, Jurayj J, George C, Gardner EL | title = Slow-onset, long-duration 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 26 | pages = 4981–92 | date = December 2000 | pmid = 11150168 | doi = 10.1021/jm000201d }}</ref>


[[File:Indatra.png|800px]]
[[File:Indatra.png|800px]]


Another method involves contraction of a dihydronaphthalene (6–6 fused system) to form the 6–5 indane skeleton.<ref>{{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 }}</ref>
Another method involves the contraction of a dihydronaphthalene (6–6 fused system) to form the 6–5 indane skeleton.<ref>{{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 }}</ref>


Routes based on a [[1-indanone]] types of intermediates are not as simple as a direct reduction of an [[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.
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.


== See also ==
== See also ==
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[[Category:Substance dependence]]
[[Category:Substance dependence]]
[[Category:Indanes]]
[[Category:1-Aminoindanes]]
[[Category:Chloroarenes]]
[[Category:Chloroarenes]]
[[Category:Serotonin-norepinephrine-dopamine reuptake inhibitors]]
[[Category:Serotonin–norepinephrine–dopamine reuptake inhibitors]]
[[Category:Stimulants]]
[[Category:Stimulants]]

Latest revision as of 19:51, 11 March 2024

Indatraline
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
  • (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)
  • Clc1ccc(cc1Cl)[C@@H]3C[C@H](NC)c2ccccc23
  • 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 checkY
  • Key:SVFXPTLYMIXFRX-BBRMVZONSA-N checkY
  (verify)

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.[1] This compound may be used to treat cocaine addictions as its effects have a slower onset and a longer duration than those of cocaine.[2] Lu 19-005 has been shown to block the action of methamphetamine and MDMA in laboratory experiments.[3]

Methylation

[edit]

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.

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.[4]

Synthesis

[edit]

Two main routes have been reported. The first route was reported by Bøgesø and co-workers.[5]

The other has been adapted to scale-up:[6]

Another method involves the contraction of a dihydronaphthalene (6–6 fused system) to form the 6–5 indane skeleton.[7]

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.

See also

[edit]

References

[edit]
  1. ^ Cho YS, Yen CN, Shim JS, Kang DH, Kang SW, Liu JO, et al. (October 2016). "Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway". Scientific Reports. 6 (1): 34655. Bibcode:2016NatSR...634655C. doi:10.1038/srep34655. PMC 5046148. PMID 27694974.
  2. ^ 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): 60–69. PMID 10490887.
  3. ^ 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): 222–227. doi:10.1002/(SICI)1098-2396(20000301)35:3<222::AID-SYN7>3.0.CO;2-K. PMID 10657029. S2CID 16190813.
  4. ^ 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.
  5. ^ 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.
  6. ^ Froimowitz M, Wu KM, Moussa A, Haidar RM, Jurayj J, George C, et al. (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.
  7. ^ 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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