RTI-336

RTI(-4229)-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] (however other sources class it as having among the faster onsets of action from among phenyltropanes[3]) 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.[4][5] RTI-336 fully substitutes for cocaine in addicted monkeys and supports self-administration,[6][7] and significantly reduces rates of cocaine use, especially when combined with SSRIs,[8] and research is ongoing to determine whether it could be a viable substitute drug in human cocaine addicts.

RTI-336
Identifiers
IUPAC name
  • 5-[(1S,3S,4S,5R)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-4-yl]-3-(4-methylphenyl)-1,2-oxazole
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC24H25ClN2O
Molar mass392.93 g·mol−1
3D model (JSmol)
SMILES
  • 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)
InChI
  • InChI=1S/C24H25ClN2O/c1-15-3-5-17(6-4-15)21-14-23(28-26-21)24-20(16-7-9-18(25)10-8-16)13-19-11-12-22(24)27(19)2/h3-10,14,19-20,22,24H,11-13H2,1-2H3/t19-,20+,22+,24-/m0/s1
  • Key:AUXUFNHAVGIVDC-IKJKNFHUSA-N

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).

RTIXR[3H]CFT[3H]Nisoxetine[3H]ParoxetineN ÷ DS ÷ D
Coc——89.13298 (1986)1045 (45)37.0111.79
177Clphenyl1.28504 (304)2420 (220)393.81891
176Mephenyl1.58398 (239)5110 (465)251.93234
354Meethyl1.62299 (180)6400 (582)184.63951
336Clp-tolyl4.091714 (1033)5741 (522)419.11404
386Mep-anisyl3.93756 (450)4027 (380)192.41025

N.B. RTI-371[9]

See also

References
  1. Carroll FI, Pawlush N, Kuhar MJ, Pollard GT, Howard JL (January 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.
  2. Carroll FI, Fox BS, Kuhar MJ, Howard JL, Pollard GT, Schenk S (December 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): 149–56. doi:10.1016/j.ejphar.2006.09.024. PMID 17067572.
  3. Kimmel HL, O'Connor JA, Carroll FI, Howell LL (January 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.
  4. Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ (March 2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal. 8 (1): E196-203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.
  5. Sofuoglu M, Kosten TR (March 2006). "Emerging pharmacological strategies in the fight against cocaine addiction". Expert Opinion on Emerging Drugs. 11 (1): 91–8. doi:10.1517/14728214.11.1.91. PMID 16503828. S2CID 9675495.
  6. Kimmel HL, O'Connor JA, Carroll FI, Howell LL (January 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.
  7. Kimmel HL, Negus SS, Wilcox KM, Ewing SB, Stehouwer J, Goodman MM, et al. (September 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): 453–62. doi:10.1016/j.pbb.2008.03.032. PMC 2453312. PMID 18468667.
  8. Howell LL, Carroll FI, Votaw JR, Goodman MM, Kimmel HL (February 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): 757–65. doi:10.1124/jpet.106.108324. PMID 17105829. S2CID 9205978.
  9. Navarro HA, Howard JL, Pollard GT, Carroll FI (April 2009). "Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter". British Journal of Pharmacology. 156 (7): 1178–84. doi:10.1111/j.1476-5381.2009.00124.x. PMC 2697692. PMID 19226282.
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