Tropoxane: Difference between revisions
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{{Short description|Chemical compound}} |
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{{cs1 config|name-list-style=vanc}} |
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{{Drugbox |
{{Drugbox |
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| verifiedrevid = |
| verifiedrevid = 448204764 |
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| IUPAC_name = |
| IUPAC_name = Methyl (1''R'',2''S'',3''S'',5''S'')-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate |
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| image = Tropoxane. |
| image = Tropoxane Structure.svg |
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| width = |
| width = |
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<!--Clinical data--> |
<!--Clinical data--> |
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| tradename = |
| tradename = |
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| routes_of_administration = |
| routes_of_administration = |
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<!--Identifiers--> |
<!--Identifiers--> |
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| CAS_number = |
| CAS_number = 192461-10-2 |
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| ATC_prefix = none |
| ATC_prefix = none |
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| ATC_suffix = |
| ATC_suffix = |
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| PubChem = 9796921 |
| PubChem = 9796921 |
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| ChemSpiderID = 7972687 |
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| ChEMBL = 5271116 |
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<!--Chemical data--> |
<!--Chemical data--> |
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| C=15 | H=16 | Cl=2 | O=3 |
| C=15 | H=16 | Cl=2 | O=3 |
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| molecular_weight = 315.192 |
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| 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 |
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| StdInChIKey = DHXANQGCRAVCSQ-PJQZNRQZSA-N |
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}} |
}} |
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'''Tropoxane''' is an aryloxytropane derivative drug developed by Organix Inc,<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> |
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== Thia analog == |
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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). |
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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. |
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For SAR purposes, a table has been included that lists some of these compounds. |
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[[File:Thia.png|400px| |
[[File:Thia.png|400px|thumb]] |
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{| border= "1" align="center" |
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|+ MAT IC<small>50</small> (nM) 8-thiabicyclo[3.2.1]octanes |
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|- cellspacing="2" bgcolor="yellow" |
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! X !! Com !! DAT !! SERT !! Com !! DAT !! SERT !! Com !! DAT !! SERT |
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<th>X</th> |
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⚫ | |||
<th>Com</th> |
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|H || 1a || 910 || >10uM || 2a || 140 || >8uM || 3a || 117 || >3uM |
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<th>DAT</th> |
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|- align="center" |
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<th>SERT</th> |
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|F || 1b || 220 || >30uM || 2b || 59 || >11uM || 3b || 38 || 494 |
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<th>Com</th> |
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|- align="center" |
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<th>DAT</th> |
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|Cl || 1c || 13 || >10uM || 2c || 11 || 1uM || 3c || 9.6 || 33 |
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<th>SERT</th> |
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|- align="center" |
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<th>Com</th> |
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|Br || 1d || 9.1 || >25uM || 2d || 6.0 || 342 || 3d || 6.0 || 14 |
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<th>DAT</th> |
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|- align="center" |
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<th>SERT</th> |
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|I || 1e || 6.7 || >8uM || 2e || 9.0 || 70 || 3e || 14 || 10 |
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|- align="center" |
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|Cl<sub>2</sub> || 1f || 4.5 || >3uM || 2f || 6.9 || 99 || 3f || 5.7 || 8.0 |
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|- align="center" |
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|BN || 1g || 8.0 || >1uM || 2g || 8.0 || 36 || 3g || 16 || 13 |
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|} |
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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. |
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<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> |
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<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> |
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<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> |
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<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> |
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<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> |
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<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> |
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<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> |
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''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? |
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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.'' |
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==2== |
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{| border= "1" align="center" |
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In this SAR, the focus is on seeing the effect of changing 8-NMe to S, O, or CH2. |
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! Enant. !! X !! Com !! DAT !! SERT !! Com !! DAT !! SERT !! Com !! DAT !! SERT |
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|- align="center" |
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| Rac || S || 1a || 4.5 || 3,600 || 2a || 6.9 || 99 || 3a || 5.7 || 8.0 |
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|- align="center" |
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| Rac || O || 1a || 10 || 6,000 || 2a || 3.1 || 64.5 || 3a || 3.3 || 6.5 |
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|- align="center" |
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| 1R || NMe || 1a || 1.2 || 867 || 2a || 0.4 || 27 || 3a || 1.1 || 2.5 |
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|- align="center" |
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| Rac || CH<sub>2</sub> || 1a || 7.1 || 5,160 || 2a || 13 || 166 || 3a || 9.6 || 33 |
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|} |
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<th>Enant.</th> |
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<th>X</th> |
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<th>Com</th> |
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<th>DAT</th> |
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<th>SERT</th> |
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<th>Com</th> |
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<th>DAT</th> |
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<th>SERT</th> |
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<th>Com</th> |
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<th>DAT</th> |
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<th>SERT</th> |
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<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> |
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<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> |
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<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> |
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<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> |
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</table> |
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* [[List of cocaine analogues]] |
* [[List of cocaine analogues]] |
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* [[O-2172]] |
* [[O-2172]] |
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==References== |
== References == |
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{{reflist}} |
{{reflist}} |
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{{Monoamine reuptake inhibitors}} |
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{{Phenyltropanes}} |
{{Phenyltropanes}} |
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{{Dopaminergics}} |
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[[Category:Dopamine reuptake inhibitors]] |
[[Category:Dopamine reuptake inhibitors]] |
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[[Category: |
[[Category:Chloroarenes]] |
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[[Category:Methyl esters]] |
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[[Category:Oxygen heterocycles]] |
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[[Category:Heterocyclic compounds with 2 rings]] |