RTI-83

RTI-83 ((–)-2β-carbomethoxy-3β-(4-ethylphenyl)tropane) is a phenyltropane derivative which represents a rare example of an SDRI or serotonin-dopamine reuptake inhibitor, a drug which inhibits the reuptake of the neurotransmitters serotonin and dopamine, while having little or no effect on the reuptake of the related neurotransmitter noradrenaline. With a binding affinity (Ki) of 55 nM at DAT and 28.4 nM at SERT but only 4030 nM at NET, RTI-83 has reasonable selectivity for DAT/SERT over NET

cis-propenyl analogue (RTI-304)
RTI-83
Clinical data
Other namesRTI-4229-83
Identifiers
IUPAC name
  • Methyl (1R,2S,3S,5S)-3-(4-ethylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC18H25NO2
Molar mass287.403 g·mol−1
3D model (JSmol)
SMILES
  • CCc3ccc(cc3)C(C1C(=O)OC)CC2CCC1N2C
InChI
  • InChI=1S/C18H25NO2/c1-4-12-5-7-13(8-6-12)15-11-14-9-10-16(19(14)2)17(15)18(20)21-3/h5-8,14-17H,4,9-11H2,1-3H3/t14-,15+,16+,17-/m0/s1
  • Key:UAMCGXVVAUEEEU-HZMVEIRTSA-N

However, further research has shown that by extending the ethyl chain even better selectivity can be achieved, with the 4′-(cis-propenyl) analogue having Ki values of 15 nM at DAT and 7.1 nM at SERT, vs 2800 nM at NET.[1][2] However RTI-436 has an even better selectivity for DAT over NET (3.09nM @ DAT & 1,960nM @ NET or a NET/DAT ratio of 634.3, but with lesser DAT/SERT equivalent potency with a ratio between them of 108) and RTI-88 has a still better ratio (984 NET/DAT with additionally having less selectivity than the former compound between DAT/SERT and having a more even spread of potency with the ratio between DAT & SERT being 88)

Binding comparison between phenyltropanes with high NET/DAT selectivity ratios
Compound DAT

[3H]WIN 35428

 5-HTT

[3H]Paroxetine

 NET

[3H]Nisoxetine

 Selectivity

5-HTT/DAT

 Selectivity

NET/DAT

RTI-8355 ± 2.128.4 ± 3.84,030 ± 3810.573.3
RTI-102474192843,4004.0691.5
RTI-30415 ± 1.27.1 ± 0.712,800 ± 3000.5186.6
RTI-881.35 ± 0.11120 ± 41,329 ± 12488.9984.0
83a* ‡1.20 ± 0.2948.7 ± 8.410,000.040.68,333.3
RTI-1434.06 ± 0.22404 ± 5640,270 ± 18099.59,919.0
*C3β-Ph-para=iodo, C2β-R=CO2-i-Pr, N8=CH2CH2CH2F
‡Compound code for phenyltropane in accord with Singh's "Chemistry, Design & SAR of cocaine antagonists" paper nomenclature, of no relation to RTI naming convention despite similarity to namesake of drug on topic.[3]

Such drugs are speculated to be useful as potential antidepressants, but few examples have been reported in the literature as yet. However, while RTI-83 has been used for binding studies to model the monoamine transporter proteins,[4] its pharmacology in vivo has not been studied in detail.

See also

References
  1. Blough BE, Abraham P, Lewin AH, Kuhar MJ, Boja JW, Carroll FI (September 1996). "Synthesis and transporter binding properties of 3 beta-(4'-alkyl-, 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2 beta-carboxylic acid methyl esters: serotonin transporter selective analogs". Journal of Medicinal Chemistry. 39 (20): 4027–35. doi:10.1021/jm960409s. PMID 8831768.
  2. Singh S (March 2000). "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256.
  3. Singh S (2010). "Chem Inform Abstract: Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists". ChemInform. 31 (20): no. doi:10.1002/chin.200020238.
  4. Roman DL, Saldaña SN, Nichols DE, Carroll FI, Barker EL (February 2004). "Distinct molecular recognition of psychostimulants by human and Drosophila serotonin transporters". The Journal of Pharmacology and Experimental Therapeutics. 308 (2): 679–87. doi:10.1124/jpet.103.057836. PMID 14593087. S2CID 6439942.
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