RTI-113

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RTI-113
Identifiers
  • Phenyl (2S,3S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
JSmol)
  • CN1C2CCC1[C@H]([C@H](C2)C3=CC=C(C=C3)Cl)C(=O)OC4=CC=CC=C4
  • InChI=1S/C21H22ClNO2/c1-23-16-11-12-19(23)20(21(24)25-17-5-3-2-4-6-17)18(13-16)14-7-9-15(22)10-8-14/h2-10,16,18-20H,11-13H2,1H3/t16?,18-,19?,20+/m1/s1 ☒N
  • Key:AAEKULYONKUBOZ-MLFFRYNPSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

RTI(-4229)-113 (2β-carbophenoxy-3β-(4-chlorophenyl)tropane) is a

phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys.[2] RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys.[3] The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered.[4] Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.[4][5]

In order for a DRI such as cocaine to induce euphoria PET scans on primates reveal that the DAT occupancy needs to be >60%.[6] Limited reinforcement may be desirable because it can help with patient compliance. DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively.[3] Whereas cocaine is a fast acting rapidly metabolized DRI, RTI-113 has a longer duration span.[7]

Self-administration graphs are inverted U-shaped. More doses of cocaine need to be administered per session than for RTI-113 because cocaine doesn't last as long as RTI-113 does. It is easy to form the rash judgement that the NRI and SRI properties of cocaine are somehow having an additive effect on provoking self-administration of cocaine.[8]

Although NRIs are known to inhibit DA reuptake in the prefrontal cortex where DATs are low in number, the fact that desipramine is not reliably self-administered makes it unlikely that NRIs are contributing to the addictive character of cocaine.[9]

The 5-HT receptors are very complex to understand and can either mediate or inhibit DA release.

However, on the whole, it is understood that synaptic 5-HT counterbalances catecholamine release.

Thus, it can said with relative certainty that the DAT is responsible for the bulk of the reinforcing effects of cocaine and related stimulants.[10]

With regard to amphetamine, a recent paper disputes this claim, and makes the point that the role of NE is completely underrated.[11]

Another paper was also recently published, seeking to address the relevance of NE in cocaine pharmacology.[12]

Transporter Selectivity

phenyltropanes with 1R,2S,3S stereochemistry.[13]
Compound [3H]
CFT
 [3H]DA [3H]Nisoxetine [3H]
NE
 [3H]Paroxetine [3H]5-HT
Cocaine[14] 89.1 275 cf. 241 3300 (1990) 119 cf. 161 1050 (45) 177 cf. 112
Troparil 23 49.8 920 (550) 37.2 1960 (178) 173
WIN 35428
 13.9 23.0 835 (503) 38.6 692 (63) 101
RTI-31 1.1 3.68 37 (22) 5.86 44.5 (4.0) 5.00
RTI-113[15] 1.98 5.25 2,926 242 2,340 391
RTI-51 1.7 ? 37.4 (23) ? 10.6 (0.96) ?
RTI-55 1.3 1.96 36 (22) 7.51 4.21 (0.38) 1.74
RTI-32 1.7 7.02 60 (36) 8.42 240 (23) 19.4

Note: cocaine has a very strong Ki value for the 5-HT3 receptor.

Threo-methylphenidate is a weaker

noradrenergic
.

Troparil is the only tropane in the above table having a [3H]NE figure that is smaller than the [3H]DA number.

References

  1. PMID 11714587
    .
  2. PMID 10640288
    .
  3. ^
    S2CID 26487942
    .
  4. ^
    PMID 18468667
    .
  5. PMID 15957006
    .
  6. PMID 11408518. Archived from the original
    (PDF) on 2006-09-21.
  7. PMID 12020686
    .
  8. S2CID 20444986
    .
  9. PMID 15526000
    .
  10. PMID 16754872
    .
  11. PMID 18811678
    .
  12. S2CID 10100028
    .
  13. PMID 7830281
    .
  14. S2CID 29377097
    .
  15. PMID 10336510
    .
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