(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane

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(-)-2β-(3-(4-Methylphenyl)isoxazol-5-yl)-3β-(4-chlorophenyl)tropane
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
Legal status
?
Identifiers
ATC code ?
PubChem CID 9800708
Chemical data
Formula C24H25ClN2O 
Mol. mass 392.920

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[edit]

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[edit]

Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse (FIC, et al. 2006).

LMAgraph.GIF
RTI336.png

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]

See also[edit]

References[edit]

  1. ^ 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
  2. ^ 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
  3. ^ 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
  4. ^ 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
  5. ^ 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
  6. ^ 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.  edit
  7. ^ 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
  8. ^ 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