Dichloropane

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Dichloropane
Dichloropane.svg
Systematic (IUPAC) name
methyl (1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate
Clinical data
Legal status
  • Legal
Identifiers
CAS Number 146725-34-0 YesY
ATC code none
PubChem CID: 127024
Chemical data
Formula C15H17Cl2NO2
Molecular mass 314.207 g/mol
  • COC(=O)[C@@H]1[C@H]2CC[C@H](N2)C[C@@H]1C3=CC(=C(C=C3)Cl)Cl
  (verify)

Dichloropane ((−)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)tropane, RTI-111, O-401) is a powerful SNDRI with IC50 (nM) values of 0.79, 3.13, and 18 at the DAT, SERT, and NET.[1]

Methylecgonidine as the direct precursor to this compound.[2]

In contrast to the closely related RTI-112, dichloropane is a potent stimulant drug which produces similar effects to cocaine as well as being structurally similar to cocaine. In animal studies although, dichloropane had a slower onset and longer duration of action.[3][4]

Transporter selectivity for disubstituted analogs

MAT IC50 (Ki) nM for 3',4'-Disubstituted Phenyltropanes.
RTI P M [3H]WIN 35,428 [3H]Paroxetine [3H]Nisoxetine
111 Cl Cl 0.79 3.13 (0.29) 18 (11)
112 Cl Me 0.82 ± 0.05 10.5 ± 0.41 (0.95 ± 0.04) 36.2 ± 1.02 (21.8 ± 0.62)
Cl Br 0.42 ± 0.02 0.78 ± 0.04 (0.19 ± 0.01) 7.24 ± 0.69 (3.62 ± 0.34)
Cl I 0.41 ± 0.09 1.39 ± 0.23 (0.34 ± 0.06) 15.1 ± 0.59 (7.74 ± 0.29)
Br Cl 0.12 ± 0.04 0.94 ± 0.09 (0.23 ± 0.02) 1.31 ± 0.13 (0.65 ± 0.07)
Br Br 0.27 ± 0.01 0.71 ± 0.03 (0.18 ± 0.01) 2.80 ± 0.16 (1.10 ± 0.08)
Br I 0.21 ± 0.06 1.14 ± 0.26 (0.25 ± 0.04) 10.4 ± 1.5 (5.12 ± 0.77)
I Cl 0.26 ± 0.05 1.04 ± 0.14 (0.63 ± 0.05) 1.26 ± 0.09 (0.63 ± 0.05)
I Br 0.20 ± 0.04 0.58 ± 0.07 (0.14 ± 0.02) 1.96 ± 0.17 (0.98 ± 0.09)
I I 0.98 ± 0.05 2.0 ± 0.56 (0.19 ± 0.05) 40.4 ± 3.56 (24 ± 2.1)
Me Me 0.43 ± 0.07 9.88 ± 1.11 (2.42 ± 0.27) 107 ± 11 (44 ± 4.7)

DAT: (p-Br, m-Cl) < (p-I, m-Br) ≈ (p-Br, m-I) ~ (p-I, m-Cl) ≈ p,m-Br2 < (p-Cl, m-I) ≈ (p-Cl, m-Br) ≈ p,m-Me2 < p,m-Cl2 < (p-Cl, m-Me) < p,m-I2.

5HT: (p-I, m-Br) < p,m-Br2 ~ (p-Cl, m-Br) < (p-Br, m-Cl) ~ (p-I, m-Cl) < (p-Br, m-I) < (p-Cl, m-I) < p,m-I2 < p,m-Cl2 < (p-Cl, m-Me) < p,m-Me2.

NET: (p-I, m-Cl) ~ (p-Br, m-Cl) < (p-I, m-Br) < p,m-Br2 < (p-Cl, m-Br) < (p-Br, m-I) < (p-Cl, m-I) < p,m-Cl2 < (p-Cl, m-Me) < p,m-I2 < p,m-Me2.

(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene

WO 9713770 
8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES
Test Compound DA uptake IC50(μM) NA uptake IC50(μM) 5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene 0.079 0.026 0.0047

Trans -CO2Me group

The thermodynamic isomer with a trans -CO2Me group is still active. This isomer was used by Neurosearch to make 3 different phenyltropanes, and all 3 were tested in clinical trials.

See also

References

  1. ↑ Carroll FI, Blough BE, Nie Z, Kuhar MJ, Howell LL, Navarro HA. Synthesis and Monoamine Transporter Binding Properties of 3-(3',4'-Disubstituted phenyl)tropane-2-carboxylic Acid Methyl Esters. J Med Chem. 2005 Apr 21;48(8):2767-71. PMID 15828814
  2. ↑ Carroll FI, Mascarella SW, Kuzemko MA, Gao Y, Abraham P, Lewin AH, Boja JW, Kuhar MJ. Synthesis, ligand binding, and QSAR (CoMFA and classical) study of 3 beta-(3'-substituted phenyl)-, 3 beta-(4'-substituted phenyl)-, and 3 beta-(3',4'-disubstituted phenyl)tropane-2 beta-carboxylic acid methyl esters. Journal of Medicinal Chemistry. 1994 Sep 2;37(18):2865-73. PMID 8071935
  3. ↑ Ranaldi R, Anderson KG, Carroll FI, Woolverton WL. Reinforcing and discriminative stimulus effects of RTI 111, a 3-phenyltropane analog, in rhesus monkeys: interaction with methamphetamine. Psychopharmacology (Berlin). 2000 Dec;153(1):103-10. PMID 11255920
  4. ↑ Cook CD, Carroll IF, Beardsley PM. Cocaine-like discriminative stimulus effects of novel cocaine and 3-phenyltropane analogs in the rat. Psychopharmacology (Berlin). 2001 Dec;159(1):58-63. PMID 11797070
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