RTI-31

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RTI-31
Chlorophenyltropane.png
Systematic (IUPAC) name
methyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
Clinical data
Legal status ?
Identifiers
CAS number 130342-80-2 YesY
ATC code ?
PubChem CID 131195
Chemical data
Formula C16H20ClNO2 
Mol. mass 293.12 g/mol
 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, although it is actually RTI-336 that entered into clinical trials with this in mind. 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. RTI-336 is actually made using RTI-31 as starting material. As will be seen in the next section, RTI-31 is not an entirely selective DRI in that it also has appreciable SERT and NET blocking affinity. RTI-31 can easily be "cleaned" though, as is done, for instance, by replacing the carbomethoxy ester with a more sterically occluded substituent such as is done for RTI-113.

Binding and Uptake Selectivity[edit]

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; 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, at least in part, through DAT blockade.

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 cf. 241 3300 (1990) 119 cf. 161 1050 (45) 177 cf. 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[edit]

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 (z-chloro-vinyl analogue).[6]

RTI-31 analogues Kozikowski, A. P.; Saiah, M. K. E.; Johnson, K. M.; Bergmann, J. S. (1995). "Chemistry and Biology of the 2.beta.-Alkyl-3.beta.-phenyl Analogs of Cocaine: Subnanomolar Affinity Ligands That Suggest a New Pharmacophore Model at the C-2 Position". Journal of Medicinal Chemistry 38 (16): 3086. doi:10.1021/jm00016a012.  edit

(i)1 N HCl, reflux 15 h; (ii) (a) POCl3, reflux; (b) MeOH, 0°C; (iii) 4-ClPhMgBr, Et2O, –40°C; (b) –78°C, 1.1 equiv TFA; (c) silica gel chromatography; (iv) DIBAL, toluene, –78°C; (v) ClCOCOCl, DCM, –78°C, DMSO, 30 min, TEA; (vi) Ph3P+CH2RBr, n-BuLi, THF, room temp; (vii) H2, Pt/C. 40 psi, cyclohexane.

R X [3H]mazindol binding [3H]dopamine uptake
CO2Me Cl 0.83 2.85
CH=CH2 Cl 0.59 2.47
(E)-CH=CHCl Cl 0.42 1.13
(Z)-CH=CHCl Cl 0.22 0.88
(E)-CH=CHPh Cl 0.31 0.66
(Z)-CH=CHPh Cl 0.14 0.31
CH2CH3 Cl 2.17 2.35
(CH2)2CH3 Cl 0.94 1.08
(CH2)2CH3 H 1.87 1.61
(CH2)3CH3 Cl 1.21 0.84
(CH2)5CH3 Cl 155.7 271
CH2CH2Ph Cl 1.46 1.54

This is because of the compounds increased lipophilicity. The act of changing a drug's duration of action through altering its lipophilicity is commonly observed and not limited to this one.

If read nocaine, interesting n-propyl group chosen,

Although no efforts have presently been made to “optimize” binding affinity at the DAT, the substantive activity found for the n-propyl derivative (−)-9 of 3 nM is remarkable; the compound is only about 10-fold less active than the best of the high-affinity tropanes in the WIN series.[7]

See also[edit]

References[edit]

  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.  edit
  3. ^ Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J. L.; Kuzemko, M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. (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 Medical 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.; Balster, R. (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, M. I.; Slemmer, J. E.; Carroll, F. I.; Martin, B. R. (1999). "Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs". The Journal of Pharmacology and Experimental Therapeutics 289 (3): 1229–1236. PMID 10336510.  edit
  6. ^ Kozikowski, A. P.; Eddine Saiah, M. K.; Johnson, K. M.; Bergmann, J. S. (1995). "Chemistry and Biology of the 2-β-Alkyl-3-β-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
  7. ^ Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.; Johnson, K. M.; Flippen-Anderson, J. L.; George, C.; Saiah, E. (1998). "Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine. Identification of Potent DAT Inhibitors Lacking the Tropane Skeleton". Journal of Medicinal Chemistry 41 (11): 1962. doi:10.1021/jm980028. PMID 9599245.  edit