Tropoxane: Difference between revisions

Browse history interactively
Page 1
Page 2
← Previous edit
Content deleted Content added
VisualWikitext
BogBot (talk | contribs)
Bots
53,132 edits
populated new fields in {{drugbox}} and reordered per bot approval. Report errors and suggestions to User_talk:BogBot
Added the cs1 style template to denote Vancouver ("vanc") citation style, because references contain "vauthors" attribute to specify the list of authors. Added s2cid. | Use this tool. Report bugs. | #UCB_Gadget
 
(27 intermediate revisions by 19 users not shown)
Line 1: Line 1:
{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc}}
{{Drugbox
{{Drugbox
| verifiedrevid = 403041615
| verifiedrevid = 448204764
| IUPAC_name = methyl (1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate
| IUPAC_name = Methyl (1''R'',2''S'',3''S'',5''S'')-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate
| image = Tropoxane.png
| image = Tropoxane Structure.svg
| width = 220
| width =


<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename =
| routes_of_administration =
| routes_of_administration =


<!--Identifiers-->
<!--Identifiers-->
| CAS_number =
| CAS_number =
| ATC_prefix = none
| ATC_prefix = none
| ATC_suffix =
| ATC_suffix =
| PubChem = 9796921
| PubChem = 9796921
| ChemSpiderID = 7972687


<!--Chemical data-->
<!--Chemical data-->
| C=15 | H=16 | Cl=2 | O=3
| C=15 | H=16 | Cl=2 | O=3
⚫
| smiles = Clc1ccc(cc1Cl)[C@H]2C[C@H]3O[C@@H]([C@H]2C(=O)OC)CC3
| molecular_weight = 315.192
| StdInChI=1S/C15H16Cl2O3/c1-19-15(18)14-10(7-9-3-5-13(14)20-9)8-2-4-11(16)12(17)6-8/h2,4,6,9-10,13-14H,3,5,7H2,1H3/t9-,10+,13+,14-/m0/s1
⚫
| smiles = COC(=O)[C@@H]1[C@H]2CC[C@H](O2)C[C@@H]1C3=CC(=C(C=C3)Cl)Cl
| StdInChIKey = DHXANQGCRAVCSQ-PJQZNRQZSA-N
}}
}}


'''Tropoxane''' is an aryloxytropane derivative drug developed by Organix Inc,<ref>[http://www.wipo.int/pctdb/en/wo.jsp?IA=US1997007744&wo=1997040859&DISPLAY=STATUS Bertha K Madras and Peter C Meltzer. Bridge-substituted Tropanes and Uses. WIPO Patent WO/1997/040859]</ref> which acts as a [[stimulant]] and potent [[dopamine]] and [[serotonin]] [[reuptake inhibitor]]. It is an analogue of [[dichloropane]] where the [[amine]] [[nitrogen]] has been replaced by an [[oxygen]] [[ether]] link (at the [[bridgehead]] position), demonstrating that the amine nitrogen is not required for [[dopamine transporter|DAT]] binding and reuptake inhibition.<ref>Madras BK, Pristupa ZB, Niznik HB, Liang AY, Blundell P, Gonzalez MD, Meltzer PC. Nitrogen-based drugs are not essential for blockade of monoamine transporters. ''Synapse''. 1996 Dec;24(4):340-8. PMID 10638825</ref><ref>Meltzer PC, Liang AY, Blundell P, Gonzalez MD, Chen Z, George C, Madras BK. 2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters. ''Journal of Medicinal Chemistry''. 1997 Aug 15;40(17):2661-73. PMID 9276012</ref><ref>Madras BK, Miller GM, Meltzer PC, Brownell AL, Fischman AJ. Molecular and regional targets of cocaine in primate brain: liberation from prosaic views. ''[[Addiction Biology]]'' 2006;5(3):351-359.</ref>
'''Tropoxane''' ('''O-1072''')<ref name="pmid10206550">{{cite journal | vauthors = Meltzer PC, Blundell P, Chen Z, Yong YF, Madras BK | title = Bicyclo[3.2.1]octanes: synthesis and inhibition of binding at the dopamine and serotonin transporters | journal = Bioorganic & Medicinal Chemistry Letters | volume = 9 | issue = 6 | pages = 857–62 | date = March 1999 | pmid = 10206550 | doi = 10.1016/s0960-894x(99)00098-0 }}</ref> is an aryloxytropane derivative drug developed by [[Organix Inc]].,<ref>{{cite patent |country= WO |number= 9740859 |status= application |title= Bridge-substituted Tropanes and Uses |pubdate= 6 November 1997 |gdate= |fdate= |pridate= |inventor= Madras BK, Meltzer PC |assign1= Harvard College }}</ref> which acts as a [[stimulant]] and potent [[dopamine]] and [[serotonin]] [[reuptake inhibitor]]. It is an analogue of [[dichloropane]] where the [[amine]] nitrogen has been replaced by an oxygen [[ether]] link (at the [[bridgehead]] position), demonstrating that the amine nitrogen is not required for [[dopamine transporter|DAT]] binding and reuptake inhibition.<ref>{{cite journal | vauthors = Madras BK, Pristupa ZB, Niznik HB, Liang AY, Blundell P, Gonzalez MD, Meltzer PC | title = Nitrogen-based drugs are not essential for blockade of monoamine transporters | journal = Synapse | volume = 24 | issue = 4 | pages = 340–8 | date = December 1996 | pmid = 10638825 | doi = 10.1002/(SICI)1098-2396(199612)24:4<340::AID-SYN4>3.0.CO;2-D | s2cid = 13410912 }}</ref><ref>{{cite journal | vauthors = Meltzer PC, Liang AY, Blundell P, Gonzalez MD, Chen Z, George C, Madras BK | title = 2-Carbomethoxy-3-aryl-8-oxabicyclo[3.2.1]octanes: potent non-nitrogen inhibitors of monoamine transporters | journal = Journal of Medicinal Chemistry | volume = 40 | issue = 17 | pages = 2661–73 | date = August 1997 | pmid = 9276012 | doi = 10.1021/jm9703045 }}</ref><ref name="pmid20575852">{{cite journal | vauthors = Madras BK, Miller GM, Meltzer PC, Brownell AL, Fischman AJ | title = Molecular and regional targets of cocaine in primate brain: liberation from prosaic views | journal = Addiction Biology | volume = 5 | issue = 3 | pages = 351–9 | date = July 2000 | pmid = 20575852 | doi = 10.1111/j.1369-1600.2000.tb00202.x | s2cid = 26252206 }}</ref>


== Thia analog ==
P. Meltzer et al. made some [http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1829488&blobtype=pdf 8-thiabicyclo(3.2.1)octanes] recently (2007).


The 8-thiabicyclo(3.2.1)octanes analogs such as [[O-4210]] have been prepared.<ref name="Pham-Huu_2007" /> A representative set of analogs is listed below.
For SAR purposes, a table has been included that lists some of these compounds.


[[File:Thia.png|400px|center]]
[[File:Thia.png|400px|thumb]]


<table border= "1" align="center">
{| border= "1" align="center"
<caption>MAT IC<small>50</small> (nM) 8-thiabicyclo[3.2.1]octanes</caption>
|+ MAT IC<small>50</small> (nM) 8-thiabicyclo[3.2.1]octanes
<tr cellspacing="2" bgcolor="yellow">
|- cellspacing="2" bgcolor="yellow"
! X !! Com !! DAT !! SERT !! Com !! DAT !! SERT !! Com !! DAT !! SERT
<th>X</th>
⚫
|- align="center"
<th>Com</th>
|H || 1a || 910 || >10uM || 2a || 140 || >8uM || 3a || 117 || >3uM
<th>DAT</th>
|- align="center"
<th>SERT</th>
|F || 1b || 220 || >30uM || 2b || 59 || >11uM || 3b || 38 || 494
<th>Com</th>
|- align="center"
<th>DAT</th>
|Cl || 1c || 13 || >10uM || 2c || 11 || 1uM || 3c || 9.6 || 33
<th>SERT</th>
|- align="center"
<th>Com</th>
|Br || 1d || 9.1 || >25uM || 2d || 6.0 || 342 || 3d || 6.0 || 14
<th>DAT</th>
|- align="center"
<th>SERT</th>
|I || 1e || 6.7 || >8uM || 2e || 9.0 || 70 || 3e || 14 || 10
|- align="center"
|Cl<sub>2</sub> || 1f || 4.5 || >3uM || 2f || 6.9 || 99 || 3f || 5.7 || 8.0
|- align="center"
|BN || 1g || 8.0 || >1uM || 2g || 8.0 || 36 || 3g || 16 || 13
|}


It had been hypothesized that transporter binding of the tropanes might include [[ionic bonding]] of the central tropane nitrogen. But it turned out that at this site neither ionic nor [[hydrogen bonding]] is a prerequisite for potent monoamine reuptake inhibition. Oxa- and thia-analogs of RTI-111 are potent inhibitors, and even an ''N''-replacement by [[Methylene (compound)|methylene]]<!--WHICH ONE?--> holds the potency within the same magnitude.<ref name="Pham-Huu_2007">{{cite journal | vauthors = Pham-Huu DP, Deschamps JR, Liu S, Madras BK, Meltzer PC | title = Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters | journal = Bioorganic & Medicinal Chemistry | volume = 15 | issue = 2 | pages = 1067–82 | date = January 2007 | pmid = 17070057 | pmc = 1829488 | doi = 10.1016/j.bmc.2006.10.016 }}</ref><ref name="pmid14612136">{{cite journal | vauthors = Madras BK, Fahey MA, Miller GM, De La Garza R, Goulet M, Spealman RD, Meltzer PC, George SR, O'Dowd BF, Bonab AA, Livni E, Fischman AJ | title = Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 41–51 | date = October 2003 | pmid = 14612136 | doi = 10.1016/j.ejphar.2003.08.055 }}</ref><ref name="pmid11746710">{{cite journal | vauthors = Goulet M, Miller GM, Bendor J, Liu S, Meltzer PC, Madras BK | title = Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates? | journal = Synapse | location = New York, N.Y. | volume = 42 | issue = 3 | pages = 129–40 | date = December 2001 | pmid = 11746710 | doi = 10.1002/syn.1108 | s2cid = 22341553 }}</ref> However, ''N''-quaternisation (''N''-dimethyl) considerably reduces DAT<!--MAT?--> affinity.
<tr align="center"><td>H</td><td>1a</td><td>910</td><td>>10uM</td><td>2a</td><td>140</td><td>>8uM</td><td>3a</td><td>117</td><td>>3uM</td></tr>
<tr align="center"><td>F</td><td>1b</td><td>220</td><td>>30uM</td><td>2b</td><td>59</td><td>>11uM</td><td>3b</td><td>38</td><td>494</td></tr>
<tr align="center"><td>Cl</td><td>1c</td><td>13</td><td>>10uM</td><td>2c</td><td>11</td><td>1uM</td><td>3c</td><td>9.6</td><td>33</td></tr>
<tr align="center"><td>Br</td><td>1d</td><td>9.1</td><td>>25uM</td><td>2d</td><td>6.0</td><td>342</td><td>3d</td><td>6.0</td><td>14</td></tr>
<tr align="center"><td>I</td><td>1e</td><td>6.7</td><td>>8uM</td><td>2e</td><td>9.0</td><td>70</td><td>3e</td><td>14</td><td>10</td></tr>
<tr align="center"><td>Cl2</td><td>1f</td><td>4.5</td><td>>3uM</td><td>2f</td><td>6.9</td><td>99</td><td>3f</td><td>5.7</td><td>8.0</td></tr>
<tr align="center"><td>BN</td><td>1g</td><td>8.0</td><td>>1uM</td><td>2g</td><td>8.0</td><td>36</td><td>3g</td><td>16</td><td>13</td></tr></table>


⚫
In this SAR, the focus is on seeing the effect of changing 8-NMe to S, O, or CH2. Both enantiomers, as well as the racemates are presented in several cases for comparison.
''It had been hypothesized that transporter binding of the tropanes might include [[ionic bonding]] of the central tropane nitrogen. But it turned out that at this site neither ionic nor [[hydrogen bonding]] is a prerequisite for potent monoamine reuptake inhibition. Oxa- and thia-analogs of RTI-111 are potent inhibitors, and even an ''N''-replacement by [[methylene]] holds the potency within the same magnitude.<ref>a) [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17070057] Synthesis of 8-thiabicyclo[3.2.1]octanes and Their Binding Affinity for the Dopamine and Serotonin Transporters. Pham-Huu D-P, Deschamps JR, Liu S, Madras BK, Meltzer PC, ''Bioorg Med Chem.'' 2007, 15(2): 1067–82. PMID 17070057<br>b) PMID 14612136 Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors. Madras BK et al. ''Eur J Pharmacol.'' 2003; 479(1-3): 41-51. c) Compare PMID 11746710 Non-amines, drugs without an amine nitrogen, potently block serotonin transport: novel antidepressant candidates?
Goulet M, Miller GM, Bendor J, Liu S, Meltzer PC, Madras BK. ''Synapse'' 2001, 42(3): 129-40.</ref> However, ''N''-quaternisation ('''N''-dimethyl') considerably reduces DAT<!--MAT?--> affinity.''


⚫
[[File:Meltzer.png|400px|thumb]]
==2==


{| border= "1" align="center"
In this SAR, the focus is on seeing the effect of changing 8-NMe to S, O, or CH2.
⚫
|+ MAT IC<small>50</small> (nM) Cl2 bicyclo[3.2.1]octanes
⚫
|- cellspacing="2" bgcolor="yellow"
! Enant. !! X !! Com !! DAT !! SERT !! Com !! DAT !! SERT !! Com !! DAT !! SERT
|- align="center"
| Rac || S || 1a || 4.5 || 3,600 || 2a || 6.9 || 99 || 3a || 5.7 || 8.0
|- align="center"
| Rac || O || 1a || 10 || 6,000 || 2a || 3.1 || 64.5 || 3a || 3.3 || 6.5
|- align="center"
| 1R || NMe || 1a || 1.2 || 867 || 2a || 0.4 || 27 || 3a || 1.1 || 2.5
|- align="center"
| Rac || CH<sub>2</sub> || 1a || 7.1 || 5,160 || 2a || 13 || 166 || 3a || 9.6 || 33
|}


⚫
== See also ==
⚫
Both enantiomers, as well as the racemates are presented in several cases for comparison.

⚫
[[File:Meltzer.png|400px|center]]

⚫
<table border= "1" align="center">
⚫
<caption>MAT IC<small>50</small> (nM) Cl2 bicyclo[3.2.1]octanes</caption>
⚫
<tr cellspacing="2" bgcolor="yellow">

<th>Enant.</th>
<th>X</th>
<th>Com</th>
<th>DAT</th>
<th>SERT</th>
<th>Com</th>
<th>DAT</th>
<th>SERT</th>
<th>Com</th>
<th>DAT</th>
<th>SERT</th>

<tr align="center"><td>Rac</td><td>S</td><td>1a</td><td>4.5</td><td>3,600</td> <td>2a</td><td>6.9</td><td>99</td><td>3a</td><td>5.7</td><td>8.0</td></tr>
<tr align="center"><td>Rac</td><td>O</td><td>1a</td><td>10</td><td>6,000</td><td>2a</td><td>3.1</td><td>64.5</td><td>3a</td><td>3.3</td><td>6.5</td></tr>
<tr align="center"><td>1R</td><td>NMe</td><td>1a</td><td>1.2</td><td>867</td><td>2a</td><td>0.4</td><td>27</td><td>3a</td><td>1.1</td><td>2.5</td></tr>
<tr align="center"><td>Rac</td><td>CH2</td><td>1a</td><td>7.1</td><td>5,160</td><td>2a</td><td>13</td><td>166</td><td>3a</td><td>9.6</td><td>33</td></tr>
</table>
⚫
==See also==
* [[List of cocaine analogues]]
* [[List of cocaine analogues]]
* [[O-2172]]
* [[O-2172]]


==References==
== References ==
{{reflist}}
{{reflist}}


⚫
{{Stimulants}}
{{Monoamine reuptake inhibitors}}
{{Phenyltropanes}}
{{Phenyltropanes}}
⚫
{{Stimulants}}
{{Dopaminergics}}


[[Category:Dopamine reuptake inhibitors]]
[[Category:Dopamine reuptake inhibitors]]
[[Category:Organochlorides]]
[[Category:Chloroarenes]]
[[Category:Methyl esters]]
[[Category:Oxygen heterocycles]]
[[Category:Heterocyclic compounds with 2 rings]]
Retrieved from "https://en.wikipedia.org/wiki/Special:ComparePages"