Tametraline: Difference between revisions

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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 437142562
| Watchedfields = changed
| IUPAC_name = (1R,4S)-N-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine
| verifiedrevid = 448234115
| image = Tametraline.png
| IUPAC_name = (1''R'',4''S'')-''N''-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine
| image = Tametraline.svg
| width = 175


<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category =
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Legal
| legal_status =


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
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| metabolism =
| metabolism =
| elimination_half-life =
| elimination_half-life =
| excretion =
| excretion =


<!--Identifiers-->
<!--Identifiers-->
| index2_label = HCl
| CAS_number = 52760-47-1
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 52795-02-5
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 = 52760-47-1
| ATC_prefix = none
| ATC_prefix = none
| ATC_suffix =
| ATC_suffix =
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| DrugBank =
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}} (HCl)
| UNII = 440C8K5Y5K
| UNII = 440C8K5Y5K
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = 2FY1A2A305
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 143316


<!--Chemical data-->
<!--Chemical data-->
| C=17 | H=19 | N=1
| C=17 | H=19 | N=1
| smiles = CN[C@H](CC1)C(C=CC=C2)=C2[C@H]1C3=CC=CC=C3
| molecular_weight = 237.339 g/mol
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| smiles = c3cccc1c3C(CCC1NC)c2ccccc2
| StdInChI = 1S/C17H19N/c1-18-17-12-11-14(13-7-3-2-4-8-13)15-9-5-6-10-16(15)17/h2-10,14,17-18H,11-12H2,1H3/t14-,17+/m0/s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = NVXPZMLRGBVYQV-WMLDXEAASA-N
}}
}}


'''Tametraline''' ('''CP-24,441''') is the parent of a series of chemical compounds investigated at [[Pfizer]] that eventually led to the development of [[sertraline]] ('''CP-51,974-1''').<ref>{{Cite pmid|6310078}}</ref>
'''Tametraline''' ('''CP-24,441''') is the parent of a series of chemical compounds investigated at [[Pfizer]] that eventually led to the development of [[sertraline]] ('''CP-51,974-1''').<ref>{{cite journal | vauthors = Koe BK, Weissman A, Welch WM, Browne RG | title = Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 226 | issue = 3 | pages = 686–700 | date = September 1983 | pmid = 6310078 }}<!--S and N are not italicized in the original title--></ref>


Sertraline has been called "3,4-dichloro tametraline". In the case of tametraline the ''cis'' diastereomers are totally impotent and are separated from the product because they are an unneeded [[contaminant]] (depressing the crystals melting point, etc).
Sertraline has been called "3,4-dichloro-tametraline". This is correct but it is an oversimplification in the sense that sertraline is the ''S'',''S''-isomer whereas tametraline is the 1''R'',4''S''-stereoisomer.


1R-Methylamino-4S-phenyl-[[tetralin]] is a potent inhibitor of NE uptake in rat brain synaptosomes,<ref>{{Cite pmid|994022}}</ref> reverses [[reserpine]] induced hypothermia in mice, and blocks uptake of [3H] into rat heart.<ref>{{Cite pmid|4427286}}</ref>
1''R''-Methylamino-4''S''-phenyl-[[tetralin]] is a potent inhibitor of norepinephrine uptake in rat brain synaptosomes,<ref>{{cite journal | vauthors = Koe BK | title = Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 199 | issue = 3 | pages = 649–61 | date = December 1976 | pmid = 994022 }}</ref> reverses [[reserpine]] induced hypothermia in mice, and blocks uptake of [[Tritium|<sup>3</sup>H]]-[[Norepinephrine]] into rat heart.<ref>{{cite journal | vauthors = Sarges R, Koe BK, Weissman A, Schaefer JP | title = Blockade of heart 3H-norepinephrine up-take by 4-phenyl-1-aminotetralines: implications for the active conformation of imipramine-like drugs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 191 | issue = 3 | pages = 393–402 | date = December 1974 | pmid = 4427286 }}</ref>


Tametraline is a [[norepinephrine-dopamine reuptake inhibitor]].<ref name="Welch">{{cite journal | vauthors = Welch WM, Kraska AR, Sarges R, Koe BK | title = Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins | journal = Journal of Medicinal Chemistry | volume = 27 | issue = 11 | pages = 1508–15 | date = November 1984 | pmid = 6492080 | doi = 10.1021/jm00377a021 }}</ref>
Tametraline is a [[catecholamine reuptake inhibitor]] that possesses certain properties that are mandatory for a [[psychostimulant]].<ref name=Welch>{{Cite pmid|6492080}}</ref> The [[benzhydryl]] moiety is an eminent feature and will remind viewers of related molecules such as [[desoxypipradrol]]. [[Indatraline]] is an indanamine analog of tetralin-based tametraline.
==Chemistry==
See also: {{US Patent|4045488}} (and refs therein: {{DOI|10.1021/ja01193a020}} {{DOI|10.1021/ja01183a058}} {{DOI|10.1021/ja01157a130}} {{DOI|10.1021/ja01635a052}})


[[Indatraline]] is an indanamine homolog of tetralin-based tametraline, although in the case of indatraline the product is pm-dichlorinated.
Two routes have been previously described,<ref name=Reinhard>{{Cite doi|10.1021/jo00897a008}}</ref> one for [[aryl]] moieties containing electron withdrawing groups, and one for electron donating groups:
[[File:Tametraline Analogs Synthesis.png|600px]]


== Law ==
"As expected, [[Friedel-Crafts]] [[cyclization]] of the diarylbutyric acid derivatives # to the most reactive ring was observed with little or none of the alternative isomer being detected.
=== Finland ===
Tametraline is completely unscheduled.


== See also ==
[[File:Tametraline synthesis.png|600px]]
* [[Cyproheptadine]] [4-(5''H''-dibenz-[a,d]cyclohepten-5-ylidine)-1-methylpiperidine]
* [[Dasotraline]]
* [[Desmethylsertraline]]
* [[EXP-561]] (1-amino-4-phenylbicyclo[2.2.2]octane)
* [[JNJ-7925476]]
* [[Lometraline]]
* [[Nefopam]]
* [[Sertraline]]


== References ==
"The [[KMnO4|KMnO<sub>4</sub>]] [[oxidation]] of the 1-aryl-tetralins # was observed to give 4-hydroxy-4-aryltetralones # instead of the expected tetralone # previously reported.<ref name=Reinhard/> As a result of this finding, direct oxidation of [[Grignard reaction]] product # was attempted and found to be a more efficient route."
{{Reflist}}


{{Stimulants}}
===CAN radical induced dimerization of styrene===
{{Monoamine reuptake inhibitors}}
"A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the [[Ceric ammonium nitrate|CAN]]-induced (see also: [http://www.organic-chemistry.org/chemicals/oxidations/ceriumammoniumnitrate-can.shtm CAN]) [[cyclodimerization]] of various [[styrene]]s in [[acetonitrile]] and [[acrylonitrile]] is described."
[http://pubs.acs.org/doi/suppl/10.1021/ol0257934/suppl_file/ol0257934_s1.pdf]
[http://www.organic-chemistry.org/abstracts/literature/609.shtm] {{DOI|10.1021/ol0257934}}


[[Category:1-Aminotetralins]]
[[File:Tam. Mech.png|400px]]
[[Category:Norepinephrine–dopamine reuptake inhibitors]]

[[Category:Drugs developed by Pfizer]]
==SAR==
Certain aromatic substitutients have a potentiating effect (e.g. ''p''-Br), whereas others negate the compounds intrinsic activity.

===Enantiopurified Trans and Cis Aminotetraline Derivatives===
{| class="wikitable"
<td colspan=8>Enantiopurified 4-aryl-aminotetralins IC<sub>50</sub> (μM)</td>
|-
|Stereo||'''X''' || '''Y''' || NE||DA ||5-HT
|-
|RS||<font color="red">'''H''' ||<font color="red">'''H''' ||0.018||0.15||0.84
|-
|SR||H||H||0.37||1.40||14.00
|-
|RS||Cl||H||0.019||0.052||0.084
|-
|SR||Cl||H||0.46||1.40||3.50
|-
|RS||Cl||Cl||0.01||0.044||0.039
|-
|SR||Cl||Cl||0.044||0.27||0.47
|-
|SS||<font color="lime">'''Cl'''||<font color="lime">'''Cl'''||1.20||1.30||0.06
|-
|RR||Cl||Cl||0.30||0.32||0.46
|}

Interestingly, (±)-sertraline is not entirely SERT selective until it has been resolved into the SS enantiomer.

C.f. "book" values:

In terms of the trans isomers there is relatively marked separation in the activity between the RS and SR enantiomers. This stands in contrast to what has been observed in the homologous indamine class where both of the trans enantiomers possessed significant TRI activity at all three of the MA transporters.

===Racemic Cis and Trans Aminotetraline Derivatives===
<table>
<tr>
<td>
{| class="wikitable"
<td colspan=8>Racemic ''trans'' 4-aryl-aminotetralins IC<sub>50</sub> (μM)</td>
|-
|R<sub>1</sub>||R<sub>2</sub>||'''X''' || '''Y''' || NE||DA ||5-HT
|-
|H||Me||<font color="red">'''H''' ||<font color="red">'''H''' ||0.04||0.21||1.48
|-
|H||Me||F||H||0.03||0.22||0.58
|-
|H||Me||Cl||H||0.03||0.10||0.12
|-
|H||Me||Br||H||0.03||0.08||0.09
|-
|H||Me||CF<sub>3</sub>||H||0.69||4.4||0.43
|-
|H||Me||H||CF<sub>3</sub>||0.26||2.60||0.39
|-
|H||Me||OMe||H||0.15||0.40||0.38
|-
|H||Me||Cl||Cl||0.02||0.06||0.05
|-
|Me||Me||H||H||0.14||0.84||0.46
|-
|Me||Me||Cl||H||0.13||0.38||0.12
|-
|Me||Me||Cl||Cl||0.04||0.17||0.04
|}
</td>
<td>
{| class="wikitable"
<td colspan=7>Racemic ''cis'' 4-aryl-aminotetralins IC<sub>50</sub> (μM)</td>
|-
|R<sub>1</sub>||R<sub>2</sub>||'''X'''||'''Y'''||5-HT||DA||NE
|-
|H||Me||H||H||3.50||5.10||1.86
|-
|H||Me||F||H||1.70||4.70||2.30
|-
|H||Me||Cl||H||0.26||1.38||1.41
|-
|H||Me||Br||H||0.19||1.60||1.40
|-
|H||Me||CF<sub>3</sub>||H||0.82||7.80||9.80
|-
|H||Me||H||CF<sub>3</sub>||0.25||2.54||2.55
|-
|H||Me||OMe||H||0.70||4.20||3.00
|-
|H||Me||Cl||Cl||0.07||0.52||0.72
|-
|Me||Me||H||H||1.6||10.0||0.31
|-
|Me||Me||Cl||H||0.24||5.60||1.16
|-
|Me||Me||Cl||Cl||0.07||2.00||0.40
|-
|H||H||Cl||Cl||0.40||1.25||0.25
|}
</td>
</tr>
</table>

Figures in brackets are for the N-dimethyl congeners. The primary amines are claimed to completely lack any affinity for the transporters.

c.f. "This property can be perceived as a potential advantage in that enhanced synaptosomal DA levels may be equated with undesirable stimulant properties of certain compounds in the trans series.<ref>{{Cite pmid|7195072}}</ref>"

==See also==
[[Image:EXPfivesixone.png|thumb|100px|[[EXP-561]] (1-amino-4-phenylbicyclo[2.2.2]octane)]]
*[[EXP-561]] (1-amino-4-phenylbicyclo[2.2.2]octane)
*[[cyproheptadine]] [4-(5H-dibenz-[a,d]cyclohepten-5-ylidine)-1-methylpiperidine]
*[[Nefopam]]
*CP-24,441 (1R, 4S-N-methyl- 4-phenyl-1,2,3,4-tetrahydro-1-naphthylamine)
*CP-39,332 (N-methyl-4-phenyl-1,2,3,4-tetrahydro-2- naphthylamine)
*[[JNJ-7925476]]

Sepracor has tried to patent the trans dichloro analog {{US patent|7105699}}

==External links==
*http://www.healyprozac.com/Book/Introduction.doc
*http://www.zoominfo.com/people/Koe_Ken_594418650.aspx
<small>During his 40 years at Pfizer, Koe authored more than 100 articles and papers.
...
Koe learned to review previous studies and to build on findings that had failed to lead to successful products. In his early work with serotonin, for example, he studied the chemical tametraline, which proved ineffective as an anti-depressant.

Tests showed the chemical functioned more as a stimulant, a use Pfizer was not interested in pursuing. Although his research had failed to yield the desired result, Koe was convinced that the development of a viable anti-depressant was within reach.</small>

==References==
{{reflist}}
{{Stimulants}}
{{Dopaminergics}}
[[Category:Serotonin-norepinephrine-dopamine reuptake inhibitors]]
[[Category:Stimulants]]
[[Category:Stimulants]]
[[Category:Amines]]
[[Category:Tetralins]]
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