(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane
![](//web.archive.org./web/20130425172932im_/http://upload.wikimedia.org/wikipedia/commons/thumb/b/bc/RTI-336.png/220px-RTI-336.png) |
Systematic (IUPAC) name |
(1R,2S,3S,5S)-8-methyl-2-(3-(4-methylphenyl)isoxazol-5-yl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octane |
Clinical data |
Pregnancy cat. |
? |
Legal status |
? |
Identifiers |
ATC code |
? |
PubChem |
CID 9800708 |
Chemical data |
Formula |
C24H25ClN2O |
Mol. mass |
392.920 |
- CC1=CC=C(C=C1)C2=NOC(=C2)[C@@H]3[C@H]4CC[C@H](N4C)C[C@@H]3C5=CC=C(C=C5)Cl
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RTI-336, (LS-193,309, (-)-2β-(3-(4-methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane) is a phenyltropane derivative which acts as a potent and selective dopamine reuptake inhibitor and stimulant drug. It binds to the dopamine transporter with around 20x the affinity of cocaine,[1] however it produces relatively mild stimulant effects, with a slow onset and long duration of action.[2] These characteristics make it a potential candidate for treatment of cocaine addiction, as a possible substitute drug analogous to how methadone is used for treating heroin abuse.[3][4] RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration,[5][6] and significantly reduces rates of cocaine use, especially when combined with SSRIs,[7] and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.
[edit] Update
Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates.
Influence of chronic dopamine transporter inhibition by RTI-336 on motor behavior, sleep and hormone levels in rhesus monkeys.
[edit] Pharmacotherapy for Cocaine Abuse
Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse (FIC, et al. 2006).
![HeteroCD.GIF](//web.archive.org./web/20130425172932im_/http://upload.wikimedia.org/wikipedia/commons/3/3c/HeteroCD.GIF)
RTI |
X |
R |
[3H]CFT |
[3H]Nisoxetine |
[3H]Paroxetine |
N ÷ D |
S ÷ D |
Coc |
— |
— |
89.1 |
3298 (1986) |
1045 (45) |
37.01 |
11.79 |
177 |
Cl |
phenyl |
1.28 |
504 (304) |
2420 (220) |
393.8 |
1891 |
176 |
Me |
phenyl |
1.58 |
398 (239) |
5110 (465) |
251.9 |
3234 |
354 |
Me |
ethyl |
1.62 |
299 (180) |
6400 (582) |
184.6 |
3951 |
336 |
Cl |
p-cresyl |
4.09 |
1714 (1033) |
5741 (522) |
419.1 |
1404 |
386 |
Me |
p-anisyl |
3.93 |
756 (450) |
4027 (380) |
192.4 |
1025 |
N.B. RTI-371[8]
[edit] See also
[edit] References
- ^ Carroll, F.; Pawlush, N.; Kuhar, M.; Pollard, G.; Howard, J. (2004). "Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes". Journal of Medicinal Chemistry 47 (2): 296–302. doi:10.1021/jm030453p. PMID 14711303. edit
- ^ Carroll, F.; Fox, B.; Kuhar, M.; Howard, J.; Pollard, G.; Schenk, S. (2006). "Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration". European Journal of Pharmacology 553 (1–3): 149–156. doi:10.1016/j.ejphar.2006.09.024. PMID 17067572. edit
- ^ Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS journal 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128. edit
- ^ Sofuoglu M, Kosten TR. Emerging pharmacological strategies in the fight against cocaine addiction. Expert Opinion on Emerging Drugs. 2006 Mar;11(1):91-98. doi:10.1517/14728214.11.1.91
- ^ Kimmel, H. .; O'Connor, J. .; Carroll, F. .; Howell, L. . (2007). "Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys". Pharmacology, Biochemistry, and Behavior 86 (1): 45–54. doi:10.1016/j.pbb.2006.12.006. PMC 1850383. PMID 17258302. edit
- ^ Kimmel, H.; Negus, S.; Wilcox, K.; Ewing, S.; Stehouwer, J.; Goodman, M.; Votaw, J.; Mello, N. et al. (2008). "Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys". Pharmacology, Biochemistry, and Behavior 90 (3): 453–462. doi:10.1016/j.pbb.2008.03.032. PMC 2453312. PMID 18468667. edit
- ^ Howell, L.; Carroll, F.; Votaw, J.; Goodman, M.; Kimmel, H. (2007). "Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys". The Journal of Pharmacology and Experimental Therapeutics 320 (2): 757–765. doi:10.1124/jpet.106.108324. PMID 17105829. edit
- ^ Navarro, H.; Howard, J.; Pollard, G.; Carroll, F. (2009). "Positive allosteric modulation of the human cannabinoid (CB1) receptor by RTI-371, a selective inhibitor of the dopamine transporter". British Journal of Pharmacology 156 (7): 1178–1184. doi:10.1111/j.1476-5381.2009.00124.x. PMC 2697692. PMID 19226282. edit
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2-Carboxymethyl Esters |
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(3,4-Disubstituted Phenyl)-tropanes |
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Arylcarboxy |
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Acyl |
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β,α Stereochemistry |
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α,β Stereochemistry |
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Heterocycles: 3-Substituted-isoxazol-5-yl |
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Heterocycles: 3-Substituted-1,2,4-oxadiazole |
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N-alkyl |
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N-replaced (S,O,C) |
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Irreversible |
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Nortropanes (N-demethylated) |
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