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RTI-83

RTI-83
Phenyltropane 11g.svg
Clinical data
Other namesRTI-4229-83
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC18H25NO2
Molar mass287.403 g·mol−1
3D model (JSmol)

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)

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-83 55 ± 2.1 28.4 ± 3.8 4,030 ± 381 0.5 73.3
RTI-102 474 1928 43,400 4.06 91.5
RTI-304 15 ± 1.2 7.1 ± 0.71 2,800 ± 300 0.5 186.6
RTI-88 1.35 ± 0.11 120 ± 4 1,329 ± 124 88.9 984.0
83a* ‡ 1.20 ± 0.29 48.7 ± 8.4 10,000.0 40.6 8,333.3
RTI-143 4.06 ± 0.22 404 ± 56 40,270 ± 180 99.5 9,919.0
*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, B. E.; Abraham, P.; Lewin, A. H.; Kuhar, M. J.; Boja, J. W.; Carroll, F. I. (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, Satendra (2010). "Chem Inform Abstract: Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists". ChemInform. 31 (20): no. doi:10.1002/chin.200020238.
  4. ^ Roman, D. L.; Saldaña, S. N.; Nichols, D. E.; Carroll, F. I.; Barker, E. L. (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.

External links