Jump to content

RTI-31: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
Citation bot (talk | contribs)
Bots
5,309,719 edits
m Removed parameters. | You can use this bot yourself. Report bugs here. | User-activated.
recategorized from Chlorobenzenes to Chlorobenzene derivatives
(14 intermediate revisions by 13 users not shown)
Line 1: Line 1:
{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
Line 10: Line 11:


<!--Identifiers-->
<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 130342-80-2
| CAS_number = 130342-80-2
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = XGP6NM44D2
| ATC_prefix =
| ATC_prefix =
| ATC_suffix =
| ATC_suffix =
Line 20: Line 23:
<!--Chemical data-->
<!--Chemical data-->
| C=16 | H=20 | Cl=1 | N=1 | O=2
| C=16 | H=20 | Cl=1 | N=1 | O=2
| molecular_weight = 293.788 g/mol
| smiles = CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)C3=CC=C(C=C3)Cl)C(=O)OC
| smiles = CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)C3=CC=C(C=C3)Cl)C(=O)OC
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
Line 28: Line 30:
}}
}}


'''(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane''' ('''RTI-''4229''-31''') is a synthetic [[structural analog|analog]] of [[cocaine]] that acts as a [[stimulant]].<ref name=Wee>{{cite journal|first1=Sunmee|last1=Wee|first2=F. Ivy|last2=Carroll|first3=William L.|last3=Woolverton|title=A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants|journal=Neuropsychopharmacology|date=15 June 2005|pages=351–362|volume=31|issue=2|doi=10.1038/sj.npp.1300795|pmid=15957006}}</ref> Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article,<ref name=Wee/> RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit self-administration in monkeys. [[WIN 35428]] was 6 x weaker than RTI-31, whereas [[RTI-51]] was 2.6 x weaker than RTI-31.
'''(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane''' ('''RTI-''4229''-31''') is a synthetic [[structural analog|analog]] of [[cocaine]] that acts as a [[stimulant]].<ref name=Wee>{{cite journal | vauthors = Wee S, Carroll FI, Woolverton WL | title = A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants | journal = Neuropsychopharmacology | volume = 31 | issue = 2 | pages = 351–62 | date = February 2006 | pmid = 15957006 | doi = 10.1038/sj.npp.1300795 | s2cid = 7224342 | doi-access = free }}</ref> Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article,<ref name=Wee/> RTI-31 is 64 times the strength of cocaine in terms of its potency to elicit self-administration in monkeys. [[WIN 35428]] was 6 times weaker than RTI-31, whereas [[RTI-51]] was 2.6 times weaker than RTI-31.


A further advantage, in addition to potency of this compound, is that its duration of activity is longer than for cocaine. It could therefore be considered within the context as an agonist based therapy for treating cocaine addiction, although it is actually [[(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane|RTI-336]] that entered into clinical trials with this in mind. RTI-31 is already completely psychoactive in its own right meaning that further chemical manipulation should be viewed as an option that is not strictly necessary. RTI-336 is actually made using RTI-31 as starting material. RTI-31 is not an entirely selective DRI in that it also has appreciable SERT and NET blocking affinity. RTI-31 can easily be "cleaned" though, as is done, for instance, by replacing the carbomethoxy ester with a more sterically occluded substituent such as is done for RTI-113.
A further advantage, in addition to potency of this compound, is that its duration of activity is longer than for cocaine. It could therefore be considered within the context as an agonist based therapy for treating cocaine addiction, although it is actually [[(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane|RTI-336]] that entered into clinical trials with this in mind. RTI-31 is already completely psychoactive in its own right meaning that further chemical manipulation should be viewed as an option that is not strictly necessary. RTI-336 is actually made using RTI-31 as starting material. RTI-31 is not an entirely selective DRI in that it also has appreciable SERT and NET blocking affinity. RTI-31 can easily be "cleaned" though, as is done, for instance, by replacing the carbomethoxy ester with a more sterically occluded substituent such as is done for RTI-113.
Line 37: Line 39:
The binding ligand affinities for the different transporters is skewed somewhat in favor of the DAT; there may be some bias in the data. The reason for this could be that WIN35428 is relatively easier to displace from the DAT versus paroxetine from the SERT, because of the higher [[binding constant]] of the former compound.
The binding ligand affinities for the different transporters is skewed somewhat in favor of the DAT; there may be some bias in the data. The reason for this could be that WIN35428 is relatively easier to displace from the DAT versus paroxetine from the SERT, because of the higher [[binding constant]] of the former compound.


Also it needs to be borne in mind the idea of transporter promiscuity.<ref>{{cite journal|first1=Lynette C.|last1=Daws|title=Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy|journal=Pharmacology & Therapeutics|date=1 January 2009|pages=89–99|volume=121|issue=1|doi=10.1016/j.pharmthera.2008.10.004|pmid=19022290|pmc=2739988}}</ref> It may be possible that the NE levels are raised, at least in part, through DAT blockade.
Also it needs to be borne in mind the idea of transporter promiscuity.<ref>{{cite journal | vauthors = Daws LC | title = Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy | journal = Pharmacology & Therapeutics | volume = 121 | issue = 1 | pages = 89–99 | date = January 2009 | pmid = 19022290 | pmc = 2739988 | doi = 10.1016/j.pharmthera.2008.10.004 }}</ref> It may be possible that the NE levels are raised, at least in part, through DAT blockade.


RTI-31 lies somewhere in the middle of the table between troparil on one end and [[RTI-55]] on the other. It is not as selective as [[RTI-113]] for the DAT, but is more selective than [[Dichloropane]] is for this transporter. RTI-31 also has some muscarinic acetylcholine agonist activity.
RTI-31 lies somewhere in the middle of the table between troparil on one end and [[RTI-55]] on the other. It is not as selective as [[RTI-113]] for the DAT, but is more selective than [[Dichloropane]] is for this transporter. RTI-31 also has some muscarinic acetylcholine agonist activity.


{| class="wikitable"
{| class="wikitable"
|colspan=7|[[Monoamine transporter|MAT]] [[IC50|IC<sub>50</sub>]] (and [[Dissociation constant|K<sub>i</sub>]]) for simple [[phenyltropanes]] with 1R,2S,3S [[stereochemistry]].<ref>{{cite journal|first1=F. Ivy|last1=Carroll|first2=Pravin|last2=Kotian|first3=Ali|last3=Dehghani|first4=Jeffrey L.|last4=Gray|title=Cocaine and 3.beta.-(4'-Substituted phenyl)tropane-2.beta.-carboxylic Acid Ester and Amide Analogs. New High-Affinity and Selective Compounds for the Dopamine Transporter|journal=Journal of Medicinal Chemistry|date=1 January 1995|pages=379–388|volume=38|issue=2|doi=10.1021/jm00002a020|pmid=7830281|first5=Michael A.|last5=Kuzemko|first6=Karol A.|last6=Parham|first7=Philip|last7=Abraham|first8=Anita H.|last8=Lewin|first9=John W.|last9=Boja|first10=Michael J.|last10=Kuhar}}</ref>
|colspan=7|[[Monoamine transporter|MAT]] [[IC50|IC<sub>50</sub>]] (and [[Dissociation constant|K<sub>i</sub>]]) for simple [[phenyltropanes]] with 1R,2S,3S [[stereochemistry]].<ref>{{cite journal | vauthors = Carroll FI, Kotian P, Dehghani A, Gray JL, Kuzemko MA, Parham KA, Abraham P, Lewin AH, Boja JW, Kuhar MJ | display-authors = 6 | title = Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter | journal = Journal of Medicinal Chemistry | volume = 38 | issue = 2 | pages = 379–88 | date = January 1995 | pmid = 7830281 | doi = 10.1021/jm00002a020 }}</ref>
|-
|-
|Compound||[<sup>3</sup>H][[WIN 35428|CFT]]||[<sup>3</sup>H][[Dopamine|DA]]||[<sup>3</sup>H][[Nisoxetine]]||[<sup>3</sup>H][[Norepinephrine|NE]]||[<sup>3</sup>H][[Paroxetine]]||[<sup>3</sup>H][[Serotonin|5-HT]]
|Compound||[<sup>3</sup>H][[WIN 35428|CFT]]||[<sup>3</sup>H][[Dopamine|DA]]||[<sup>3</sup>H][[Nisoxetine]]||[<sup>3</sup>H][[Norepinephrine|NE]]||[<sup>3</sup>H][[Paroxetine]]||[<sup>3</sup>H][[Serotonin|5-HT]]
|-
|-
|[[Cocaine]]<ref>{{cite journal|first1=Alan P.|last1=Kozikowski|first2=Kenneth M.|last2=Johnson|first3=Olivier|last3=Deschaux|first4=Bidhan C.|last4=Bandyopadhyay|title=Mixed Cocaine Agonist/Antagonist Properties of (+)-Methyl 4β-(4-Chlorophenyl)-1-methylpiperidine-3α-carboxylate, a Piperidine-Based Analog of Cocaine|url=http://jpet.aspetjournals.org/content/305/1/143.full|journal=Journal of Pharmacology and Experimental Therapeutics|date=1 April 2003|pages=143–150|volume=305|issue=1|doi=10.1124/jpet.102.046318|pmid=12649362|first5=Gian Luca|last5=Araldi|first6=Gilberto|last6=Carmona|first7=Patrik|last7=Munzar|first8=Miles P.|last8=Smith|first9=Robert L.|last9=Balster|first10=Patrick M.|last10=Beardsley|first11=Srihari R.|last11=Tella}}</ref>||89.1||<span style="color:red;">275 [[cf.]] 241</span>||3300 (1990)||<span style="color:red;">119 cf. 161</span>||1050 (45)||<span style="color:red;">177 cf. 112</span>
|[[Cocaine]]<ref>{{cite journal | vauthors = Kozikowski AP, Johnson KM, Deschaux O, Bandyopadhyay BC, Araldi GL, Carmona G, Munzar P, Smith MP, Balster RL, Beardsley PM, Tella SR | display-authors = 6 | title = Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 305 | issue = 1 | pages = 143–50 | date = April 2003 | pmid = 12649362 | doi = 10.1124/jpet.102.046318 }}</ref>||89.1||<span style="color:red;">275 [[cf.]] 241</span>||3300 (1990)||<span style="color:red;">119 cf. 161</span>||1050 (45)||<span style="color:red;">177 cf. 112</span>
|-
|-
|[[Troparil]]||23||<span style="color:red;">49.8</span>||920 (550)||<span style="color:red;">37.2</span>||1960 (178)||<span style="color:red;">173</span>
|[[Troparil]]||23||<span style="color:red;">49.8</span>||920 (550)||<span style="color:red;">37.2</span>||1960 (178)||<span style="color:red;">173</span>
Line 54: Line 56:
|RTI-31||1.1||<span style="color:red;">3.68</span>||37 (22)||<span style="color:red;">5.86</span>||44.5 (4.0)||<span style="color:red;">5.00</span>
|RTI-31||1.1||<span style="color:red;">3.68</span>||37 (22)||<span style="color:red;">5.86</span>||44.5 (4.0)||<span style="color:red;">5.00</span>
|-
|-
|[[RTI-113]]<ref>{{cite journal|first1=M. I.|last1=Damaj|first2=J. E.|last2=Slemmer|first3=F. I.|last3=Carroll|first4=B. R.|last4=Martin|title=Pharmacological Characterization of Nicotine's Interaction with Cocaine and Cocaine Analogs|url=http://jpet.aspetjournals.org/content/289/3/1229.long|journal=Journal of Pharmacology and Experimental Therapeutics|date=1 June 1999|pages=1229–1236|volume=289|issue=3|pmid=10336510}}</ref>||1.98||<span style="color:red;">5.25</span>||2,926||<span style="color:red;">242</span>||2,340||<span style="color:red;">391</span>
|[[RTI-113]]<ref>{{cite journal | vauthors = Damaj MI, Slemmer JE, Carroll FI, Martin BR | title = Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 289 | issue = 3 | pages = 1229–36 | date = June 1999 | pmid = 10336510 | url = http://jpet.aspetjournals.org/content/289/3/1229.long }}</ref>||1.98||<span style="color:red;">5.25</span>||2,926||<span style="color:red;">242</span>||2,340||<span style="color:red;">391</span>
|-
|-
|[[RTI-51]]||1.7||<span style="color:red;">?</span>||37.4 (23)||<span style="color:red;">?</span>||10.6 (0.96)||<span style="color:red;">?</span>
|[[RTI-51]]||1.7||<span style="color:red;">?</span>||37.4 (23)||<span style="color:red;">?</span>||10.6 (0.96)||<span style="color:red;">?</span>
Line 65: Line 67:
Data in Above table from rats brains (1995). More recent work has advocated using cloned human transporters.
Data in Above table from rats brains (1995). More recent work has advocated using cloned human transporters.


==Additional Analogs==
== See also ==
===RTI===
[[File:RTI-470 structure.png|thumb|right|200px|RTI-470 structure:<ref>{{Cite journal|pmid=16584128|pmc=2751440|year=2006|author1=Carroll|first1=F. I.|title=Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse|journal=The AAPS Journal|volume=8|issue=1|pages=E196–203|last2=Howard|first2=J. L.|last3=Howell|first3=L. L.|last4=Fox|first4=B. S.|last5=Kuhar|first5=M. J.|doi=10.1208/aapsj080124}}</ref>]]
*Nor-RTI-31 is called RTI-110.<ref>{{Cite journal|pmid=7205634|year=1981|author1=Spealman|first1=R. D.|title=Self-administration of cocaine derivatives by squirrel monkeys|journal=The Journal of Pharmacology and Experimental Therapeutics|volume=216|issue=3|pages=532–6|last2=Kelleher|first2=R. T.}}</ref>
*Reduced ester to alcohol is called RTI-93.
*Acetylated alcohol is called RTI-105.
*Benzoyl alcohol is called RTI-123.
*RTI-145 is a methyl carbonate of the alcohol.
Conversion of ester in RTI-31 to heteroaromatic nuclei also possible.
E.g. RTI-470 was among the potent DRI known to exist, 0.094nM.

===Kozikowski===
Further chemical modification of RTI-31 leads to novel chemical entities; some of them are highly potent, and one of them has been reported as lasting for three days (''z''-chloro-vinyl analogue).<ref>{{cite journal|first1=Alan P.|last1=Kozikowski|first2=Marinella|last2=Roberti|first3=Kenneth M.|last3=Johnson|first4=John S.|last4=Bergmann|title=SAR of cocaine: further exploration of structural variations at the C-2 center provides compounds of subnanomolar binding potency|url=http://www.sciencedirect.com/science/article/pii/S0960894X00803418|journal=Bioorganic & Medicinal Chemistry Letters|date=1 June 1993|pages=1327–1332|volume=3|issue=6|doi=10.1016/S0960-894X(00)80341-8|first5=Richard G.|last5=Ball}}</ref><ref>{{cite journal|first1=Alan P.|last1=Kozikowski|first2=M. K. Eddine|last2=Saiah|first3=Kenneth M.|last3=Johnson|first4=John S.|last4=Bergmann|title=Chemistry and Biology of the 2.beta.-Alkyl-3.beta.-phenyl Analogs of Cocaine: Subnanomolar Affinity Ligands That Suggest a New Pharmacophore Model at the C-2 Position|journal=Journal of Medicinal Chemistry|date=1 August 1995|pages=3086–3093|volume=38|issue=16|doi=10.1021/jm00016a012|pmid=7636872}}</ref>
[[File:Compound 5.png|100px]]

[[File:RTI-31 analogues.svg|thumb|center|800px|RTI-31 analogues {{Cite journal | doi = 10.1021/jm00016a012| title = Chemistry and Biology of the 2.beta.-Alkyl-3.beta.-phenyl Analogs of Cocaine: Subnanomolar Affinity Ligands That Suggest a New Pharmacophore Model at the C-2 Position| journal = Journal of Medicinal Chemistry| volume = 38| issue = 16| pages = 3086–93| year = 1995| last1 = Kozikowski | first1 = A. P. | last2 = Saiah | first2 = M. K. E. | last3 = Johnson | first3 = K. M. | last4 = Bergmann | first4 = J. S. | pmid=7636872}}]]
(i)1 N HCl, reflux 15 h; (ii) (a) POCl<sub>3</sub>, reflux; (b) MeOH, 0&nbsp;°C; (iii) 4-ClPhMgBr, Et<sub>2</sub>O, –40&nbsp;°C; (b) –78&nbsp;°C, 1.1 equiv TFA; (c) silica gel chromatography; (iv) DIBAL, toluene, –78&nbsp;°C; (v) ClCOCOCl, DCM, –78&nbsp;°C, DMSO, 30 min, TEA; (vi) Ph<sub>3</sub>P<sup>+</sup>CH<sub>2</sub>RBr<sup>−</sup>, n-BuLi, THF, room temp; (vii) H<sub>2</sub>, Pt/C. 40 psi, cyclohexane.

{| class="wikitable"
|R||X||[<sup>3</sup>H]mazindol binding||[<sup>3</sup>H]dopamine uptake
|-
||CO<sub>2</sub>Me||Cl||0.83||2.85
|-
||CH=CH<sub>2</sub>||Cl||0.59||2.47
|-
||(''E'')-CH=CHCl||Cl||0.42||1.13
|-
||(''Z'')-CH=CHCl||Cl||0.22||0.88
|-
||(''E'')-CH=CHPh||Cl||0.31||0.66
|-
||(''Z'')-CH=CHPh||Cl||0.14||0.31
|-
||CH<sub>2</sub>CH<sub>3</sub>||Cl||2.17||2.35
|-
||(CH<sub>2</sub>)<sub>2</sub>CH<sub>3</sub>||Cl||0.94||1.08
|-
||(CH<sub>2</sub>)<sub>2</sub>CH<sub>3</sub>||H||1.87||1.61
|-
||(CH<sub>2</sub>)<sub>3</sub>CH<sub>3</sub>||Cl||1.21||0.84
|-
||(CH<sub>2</sub>)<sub>5</sub>CH<sub>3</sub>||Cl||155.7||271
|-
||CH<sub>2</sub>CH<sub>2</sub>Ph||Cl||1.46||1.54
|}

This is because of the compounds increased [[lipophilicity]]. The act of changing a drug's duration of action through altering its lipophilicity is commonly observed and not limited to this one.

If read [[nocaine]], interesting ''n''-propyl group chosen,

{{cquote|Although no efforts have presently been made to “optimize” binding affinity at the DAT, the substantive activity found for the ''n''-propyl derivative (−)-9 of 3 nM is remarkable; the compound is only about 10-fold less active than the best of the high-affinity tropanes in the WIN series.<ref>{{cite journal|first1=Alan P.|last1=Kozikowski|first2=Gian Luca|last2=Araldi|first3=John|last3=Boja|first4=William M.|last4=Meil|title=Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine. Identification of Potent DAT Inhibitors Lacking the Tropane Skeleton|journal=Journal of Medicinal Chemistry|date=1 May 1998|pages=1962–1969|volume=41|issue=11|doi=10.1021/jm980028|pmid=9599245|first5=Kenneth M.|last5=Johnson|first6=Judith L.|last6=Flippen-Anderson|first7=Clifford|last7=George|first8=Eddine|last8=Saiah}}</ref>}}

==See also==
*[[(+)-CPCA]]
*[[(+)-CPCA]]
*[[(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane|RTI-336]]
*[[(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane|RTI-336]]
Line 123: Line 73:


== References ==
== References ==
{{reflist}}
{{reflist|32em}}


{{Phenyltropanes}}
{{Phenyltropanes}}
Line 133: Line 83:
[[Category:Dopamine reuptake inhibitors]]
[[Category:Dopamine reuptake inhibitors]]
[[Category:Sympathomimetic amines]]
[[Category:Sympathomimetic amines]]
[[Category:Chloroarenes]]
[[Category:Chlorobenzene derivatives]]

Revision as of 01:42, 4 February 2024

RTI-31
Identifiers
  • Methyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H20ClNO2
Molar mass293.79 g·mol−1
3D model (JSmol)
  • CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)C3=CC=C(C=C3)Cl)C(=O)OC
  • InChI=1S/C16H20ClNO2/c1-18-12-7-8-14(18)15(16(19)20-2)13(9-12)10-3-5-11(17)6-4-10/h3-6,12-15H,7-9H2,1-2H3/t12-,13+,14+,15-/m0/s1 ☒N
  • Key:ZEOHVQFWFVMPGM-YJNKXOJESA-N ☒N
 ☒NcheckY (what is this?)  (verify)

(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-4229-31) is a synthetic analog of cocaine that acts as a stimulant.[1] Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article,[1] RTI-31 is 64 times the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN 35428 was 6 times weaker than RTI-31, whereas RTI-51 was 2.6 times weaker than RTI-31.

A further advantage, in addition to potency of this compound, is that its duration of activity is longer than for cocaine. It could therefore be considered within the context as an agonist based therapy for treating cocaine addiction, although it is actually RTI-336 that entered into clinical trials with this in mind. RTI-31 is already completely psychoactive in its own right meaning that further chemical manipulation should be viewed as an option that is not strictly necessary. RTI-336 is actually made using RTI-31 as starting material. RTI-31 is not an entirely selective DRI in that it also has appreciable SERT and NET blocking affinity. RTI-31 can easily be "cleaned" though, as is done, for instance, by replacing the carbomethoxy ester with a more sterically occluded substituent such as is done for RTI-113.

Binding and uptake selectivity

Based on the uptake of tritiated biogenic monoamine radiotracers it can be confirmed by observing the figures in the attached table that RTI-31 is a relatively balanced reuptake inhibitor wrt the D/N/S ratio.

The binding ligand affinities for the different transporters is skewed somewhat in favor of the DAT; there may be some bias in the data. The reason for this could be that WIN35428 is relatively easier to displace from the DAT versus paroxetine from the SERT, because of the higher binding constant of the former compound.

Also it needs to be borne in mind the idea of transporter promiscuity.[2] It may be possible that the NE levels are raised, at least in part, through DAT blockade.

RTI-31 lies somewhere in the middle of the table between troparil on one end and RTI-55 on the other. It is not as selective as RTI-113 for the DAT, but is more selective than Dichloropane is for this transporter. RTI-31 also has some muscarinic acetylcholine agonist activity.

MAT IC50 (and Ki) for simple phenyltropanes with 1R,2S,3S stereochemistry.[3]
Compound [3H]CFT [3H]DA [3H]Nisoxetine [3H]NE [3H]Paroxetine [3H]5-HT
Cocaine[4] 89.1 275 cf. 241 3300 (1990) 119 cf. 161 1050 (45) 177 cf. 112
Troparil 23 49.8 920 (550) 37.2 1960 (178) 173
WIN 35428 13.9 23.0 835 (503) 38.6 692 (63) 101
RTI-31 1.1 3.68 37 (22) 5.86 44.5 (4.0) 5.00
RTI-113[5] 1.98 5.25 2,926 242 2,340 391
RTI-51 1.7 ? 37.4 (23) ? 10.6 (0.96) ?
RTI-55 1.3 1.96 36 (22) 7.51 4.21 (0.38) 1.74
RTI-32 1.7 7.02 60 (36) 8.42 240 (23) 19.4

Data in Above table from rats brains (1995). More recent work has advocated using cloned human transporters.

See also

References

  1. ^ a b Wee S, Carroll FI, Woolverton WL (February 2006). "A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants". Neuropsychopharmacology. 31 (2): 351–62. doi:10.1038/sj.npp.1300795. PMID 15957006. S2CID 7224342.
  2. ^ Daws LC (January 2009). "Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & Therapeutics. 121 (1): 89–99. doi:10.1016/j.pharmthera.2008.10.004. PMC 2739988. PMID 19022290.
  3. ^ Carroll FI, Kotian P, Dehghani A, Gray JL, Kuzemko MA, Parham KA, et al. (January 1995). "Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter". Journal of Medicinal Chemistry. 38 (2): 379–88. doi:10.1021/jm00002a020. PMID 7830281.
  4. ^ Kozikowski AP, Johnson KM, Deschaux O, Bandyopadhyay BC, Araldi GL, Carmona G, et al. (April 2003). "Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine". The Journal of Pharmacology and Experimental Therapeutics. 305 (1): 143–50. doi:10.1124/jpet.102.046318. PMID 12649362.
  5. ^ Damaj MI, Slemmer JE, Carroll FI, Martin BR (June 1999). "Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs". The Journal of Pharmacology and Experimental Therapeutics. 289 (3): 1229–36. PMID 10336510.
Retrieved from "https://en.wikipedia.org/w/index.php?title=RTI-31&oldid=1203024498"