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RTI-177

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RTI-177
Systematic (IUPAC) name
5-[(1R,2S,3S,

5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-3-(4- methylphenyl)-1,2-oxazole

Identifiers
ATC code  ?
PubChem CID 9800708
ChEMBL CHEMBL298580 YesY
Chemical data
Formula C24H25ClN2O 
Mol. mass 392.92 g/mol
SMILES eMolecules & PubChem
Therapeutic considerations
Pregnancy cat.  ?
Legal status  ?

RTI-177 (2β-(3-phenylisoxazol-5-yl)-3β-(4-chlorophenyl)tropane, β-CPPIT) is a synthetic stimulant drug from the phenyltropane family, which acts as a DRI with micromolar affinity for the SERT.[1] RTI-177 has an unusually long duration of action of 20 hours or more, substantially longer than the related compound RTI-336 from which it differs in molecular structure only by the absence of a p-methyl group.[2]

"the nonselective monoamine transporter inhibitor RTI-126 and the DAT-selective inhibitors RTI-150 and RTI-336 both had a faster rate of onset (30 min) and a short duration of action (4h). In contrast, the nonselective monoamine transporter inhibitor RTI-112 had a slower rate of onset (30–60 min) and a longer duration of action (10h). The DAT-selective inhibitors RTI-171 and RTI-177 also had slower rates of onset (30–120 min), but RTI-171 had a short duration of action (2.5 h) while RTI-177 had a very long duration of action (20 h)."[3]

Comparison of six MAT inhibitors

RTI X R [3H]CFT [3H]Nisoxetine [3H]Paroxetine
Coc 89.1 3298 (1986) 1045 (45)
177 Cl phenyl 1.28 504 (304) 2420 (220)
176 Me phenyl 1.58 398 (239) 5110 (465)
354 Me ethyl 1.62 299 (180) 6400 (582)
336 Cl p-cresyl 4.09 1714 (1033) 5741 (522)
386 Me p-anisoyl 3.93 756 (450) 4027 (380)
LMAgraph.GIF
RTI336.png

HeteroCD.GIF

In the Lindsey paper, RTI-177 was wrongly considered to be a dual inhibitor of the NET, although this was later found out to be incorrect (despite being written in plain English).[weasel words]

"In acute toxicity studies in male rats, 3β-(4-chlorophenyl)-2β-[3-(4’-methylphenyl)isoxazol-5-yl]tropane (RTI-336) possessed an LD50 of 180 mg/kg after oral administration, compared with 49 mg/kg for RTI-177 (unpublished results, Howell 2005; Table 9). These results suggested that RTI-336 was a better candidate than RTI-177 for further preclinical development."[2]

Also the potency of the heterocyclic compounds is not as great as would be predicted based on in vitro test results.

References

  1. ^ [1] Lindsey, K.P., Wilcox, K.M., Votaw, J.R., Goodman, M.M., Plisson, C., Carroll, F.I., Rice, K.C., Howell, L.L. Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging. Journal of Pharmacology and Experimental Therapeutics, 309: 959-969, 2004.
  2. ^ a b [2] Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ. Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse. AAPS J. 2006 Mar 24;8(1):E196-203.
  3. ^ [3] Kimmel HL, O'Connor JA, Carroll FI, Howell LL. Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys. Pharmacol Biochem Behav. 2007 Jan;86(1):45-54.

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