Salicylmethylecgonine

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Salicylmethylecgonine
Legal status
Legal status
Identifiers
  • methyl (1R,2R,3S,5S)-3-(2-hydroxybenzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate
JSmol)
SMILES
  • CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)OC(=O)C3=CC=CC=C3O)C(=O)OC
  • InChI=1S/C17H21NO5/c1-18-10-7-8-12(18)15(17(21)22-2)14(9-10)23-16(20)11-5-3-4-6-13(11)19/h3-6,10,12,14-15,19H,7-9H2,1-2H3/t10-,12+,14-,15+/m0/s1
  • Key:PEISRHQJLATJPJ-MMMKDXCPSA-N
  (verify)

Salicylmethylecgonine, (2′-Hydroxycocaine) is a

QSAR of a 10-fold increase over cocaine in its binding potency for the dopamine transporter & a 52-fold enhanced affinity for the norepinephrine transporter. It also has a reduced selectivity for the serotonin transporter though only due to its greater increase at NET binding; its SERT affinity being 4-fold increased compared to cocaine.[3]
However, in overall binding affinity (not uptake inhibition) it displaces ligands better across the board than cocaine in all monoamine categories.

Binding comparison between cocaine and semi-synthetic derivative o-hydroxy-cocaine[4]
Compound DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

Cocaine 249 ± 37 615 ± 120 2500 ± 70 2.5 10.0
2′(ortho)-hydroxycocaine 25 ± 4 143 ± 21 48 ± 2 5.7 1.9

Study of molecular modeling inferred that, in addition to intramolecular hydrogen bonding between the adjacent 3β-carbonyl and the 2′-OH ortho group of 185d (i.e. salicylmethylecgonine), that intermolecular hydrogen bonding between its hydroxy ortho substituent and the dopamine transporter was also possible; and was rationalized to be due to its nearness of where the nitrogen and oxygen atoms reside in the para-hydroxy of dopamine itself and its own intrinsic relation to DAT whereby that mutual hydroxyl functionality is mediated in both salicylmethylecgonine and dopamine in a similar manner. That is, at serine residue 359 on DAT, as the distance of the hydroxy to the bridge-nitrogen on salicylmethylecgonine is 7.96 Å (close to that of the distance between the p-OH & the NH2 atoms of dopamine, their distance apart being 7.83 Å). Which may play a role in this analogs increased behavioral stimulation over its parent compound cocaine. The meta-hydroxy group of dopamine, by contrast, has a distance of 6.38 Å from its nitrogen and is believed to engage with the 356 residue on DAT.[4]

See also

References

  1. doi:10.1080/00397919708005923
    .
  2. S2CID 41556606
    .
  3. ^
    S2CID 24348794
    .
  4. ^
    PMID 11749256
    .
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