(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane
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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 |
Legal status |
? |
Identifiers |
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ATC code |
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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.
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.
Pharmacotherapy for Cocaine Abuse
Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse (FIC, et al. 2006).
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]
See also
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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Kimmel, Heather L.; Negus, S. Stevens; Wilcox, Kristin M.; Ewing, Sarah B.; Stehouwer, Jeffrey; Goodman, Mark M.; Votaw, John R.; Mello, Nancy K.; Carroll, F. Ivy; Howell, Leonard L. (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.
- ↑ 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.
- ↑ 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.
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| (3,4-Disubstituted Phenyl)-tropanes | |
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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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