RTI-31

RTI-31
Systematic (IUPAC) name
methyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
Clinical data
Pregnancy cat.  ?
Legal status  ?
Identifiers
CAS number 130342-80-2
ATC code  ?
PubChem CID 131195
Chemical data
Formula C16H20ClNO2 
Mol. mass 293.12 g/mol
SMILES eMolecules & PubChem
 YesY(what is this?)  (verify)

(–)-2β-Carbomethoxy-3β-(4'-chlorophenyl)tropane (RTI-31) is a synthetic analog of cocaine that acts as a stimulant.[1] Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article,[1] RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit self-administration in monkeys. WIN 35428 was 6 x weaker than RTI-31, whereas RTI-51 was 2.6 x weaker than RTI-31.

A further advantage, in addition to potency of this compound, is that its duration of activity is longer than for cocaine. It could therefore be considered within the context as an agonist based therapy for treating cocaine addiction (c.f. ritalin). This is a valid idea but the fact that these compounds have reinforcing properties which render their use addictive has served as a barrier to their introduction. RTI-31 one day might become available for use on humans, although in the mean time the related compound/s tesofensine and brasofensine are being pursued instead.

It should be noted that RTI-31 is already completely psychoactive in its own right meaning that further chemical manipulation should be viewed as an option that is not strictly necessary.

Contents

Binding and Uptake Selectivity

Based on the uptake of tritiated biogenic monoamine radiotracers it can be confirmed by observing the figures in the attached table that RTI-31 is a relatively balanced reuptake inhibitor wrt the D/N/S ratio.

The binding ligand affinities for the different transporters is skewed somewhat in favor of the DAT. Private discussion with F. Ivy Carroll led to confirmation that there may be some bias in the data. The reason for this could be that WIN35428 is relatively easier to displace from the DAT versus paroxetine from the SERT, because of the higher binding constant of the former compound.

Also it needs to be borne in mind the idea of transporter promiscuity.[2] It may be possible that the NE levels are raised through DAT blockade alone (or mostly), and that little (if any) blockade of the NET is necessary to bring about this change.

RTI-31 lies somewhere in the middle of the table between troparil on one end and RTI-55 on the other. It is not as selective as RTI-113 for the DAT, but is more selective than RTI-111 is for this transporter. RTI-31 also has some muscarinic acetylcholine agonist activity.

MAT IC50 (and Ki) for simple phenyltropanes with 1R,2S,3S stereochemistry.[3]
Compound [3H]CFT [3H]DA [3H]Nisoxetine [3H]NE [3H]Paroxetine [3H]5-HT
Cocaine[4] 89.1 275 c.f. 241 3300 (1990) 119 c.f. 161 1050 (45) 177 c.f. 112
WIN 35,065-2 23 49.8 920 (550) 37.2 1960 (178) 173
WIN 35,428 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[5] 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

Data in Above table from rats brains (1995). More recent work has advocated using cloned human transporter/s.

Additional Analogs

Further chemical modification of RTI-31 leads to novel chemical entities; some of them are highly potent, and one of them has been reported as lasting for three days.[6] This is because of the compounds impressive lipophilicity. The act of changing a drugs duration of action through altering its lipophilicity is commonly observed and not limited to this one. There are many examples of this occurring, for instance, compare Ritalin with pipradrol and finally desoxypipradrol. Additionally, drugs such as sibutramine were shown to have quite a long time of stay in the body if the dosing was daily and chronic over a period of several days/weeks.

RTI-31 is also used in the synthesis of other compounds such as RTI-113 and RTI-336.

References

  1. ^ a b Wee, S.; Carroll, F.; Woolverton, W. (2006). "A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants". Neuropsychopharmacology 31 (2): 351–362. doi:10.1038/sj.npp.1300795. PMID 15957006.  edit
  2. ^ Daws, L. (2009). "Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & therapeutics 121 (1): 89–99. doi:10.1016/j.pharmthera.2008.10.004. PMC 2739988. PMID 19022290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2739988.  edit
  3. ^ Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J. L.; Kuzemko, M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H. et al. (1995). "Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter". Journal of medicinal chemistry 38 (2): 379–388. doi:10.1021/jm00002a020. PMID 7830281.  edit
  4. ^ Kozikowski, A. .; Johnson, K. .; Deschaux, O. .; Bandyopadhyay, B. .; Araldi, G. .; Carmona, G. .; Munzar, P. .; Smith, M. . et al. (2003). "Mixed cocaine agonist/antagonist properties of (+)-methyl 4beta-(4-chlorophenyl)-1-methylpiperidine-3alpha-carboxylate, a piperidine-based analog of cocaine". The Journal of pharmacology and experimental therapeutics 305 (1): 143–150. doi:10.1124/jpet.102.046318. PMID 12649362.  edit
  5. ^ Damaj, MI; Slemmer; Carroll; Martin (1999). "Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs". The Journal of pharmacology and experimental therapeutics 289 (3): 1229–36. PMID 10336510.  edit
  6. ^ Kozikowski, A. P.; Eddine Saiah, M. K.; Johnson, K. M.; Bergmann, J. S. (1995). "Chemistry and biology of the 2 beta-alkyl-3 beta-phenyl analogues of cocaine: subnanomolar affinity ligands that suggest a new pharmacophore model at the C-2 position". Journal of Medicinal Chemistry 38 (16): 3086–3093. doi:10.1021/jm00016a012. PMID 7636872.  edit

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See also