Salicylmethylecgonine

Salicylmethylecgonine
Identifiers
IUPAC name
  • methyl (1R,2R,3S,5S)-3-(2-hydroxybenzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC17H21NO5
Molar mass319.357 g·mol−1
3D model (JSmol)
SMILES
  • CN1[C@H]2CC[C@@H]1[C@H]([C@H](C2)OC(=O)C3=CC=CC=C3O)C(=O)OC
InChI
  • 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 tropane derivative drug which is both a synthetic analogue and a possible active metabolite of cocaine.[1] Its potency in vitro is around 10x that of cocaine,[2] although it is only around three times more potent than cocaine when administered to mice (likely owing to it having a higher LogP: 2.89 than that of cocaine: 2.62)[3] Note however that the compound 2′-Acetoxycocaine would act as a prodrug to Salicylmethylecgonine in humans, and has a more efficient partition coefficient which would act as a delivery system and would circumvent this reason for a loss in potency. Salicylmethylecgonine also shows increased behavioral stimulation compared to cocaine similar to the phenyltropanes.[4] The hydroxy branch renders the molecule 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

Cocaine249 ± 37615 ± 1202500 ± 702.510.0
2′(ortho)-hydroxycocaine25 ± 4143 ± 2148 ± 25.71.9

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. ↑ Singh S, Basmadjian GP, Avor K, Pouw B, Seale TW (1997). "A convenient synthesis of 2'- or 4'-hydroxycocaine". Synthetic Communications. 27 (22): 4003–4012. doi:10.1080/00397919708005923.
  2. ↑ el-Moselhy TF, Avor KS, Basmadjian GP (September 2001). "2'-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies". Archiv der Pharmazie. 334 (8–9): 275–8. doi:10.1002/1521-4184(200109)334:8/9<275::aid-ardp275>3.0.co;2-b. PMID 11688137.
  3. 1 2 Seale TW, Avor K, Singh S, Hall N, Chan HM, Basmadjian GP (November 1997). "2'-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding". NeuroReport. 8 (16): 3571–5. doi:10.1097/00001756-199711100-00030. PMID 9427328. S2CID 24348794.
  4. 1 2 3 Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Satendra Singh et al. Chem. Rev. 2000, 100. 925-1024. PubMed; Chemical Reviews (Impact Factor: 45.66). 04/2000; 100(3):925-1024 American Chemical Society; 2000 ISSN 0009-2665 ChemInform; May, 16th 2000, Volume 31, Issue 20, doi:10.1002/chin.200020238. Mirror hotlink.
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