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| Formula | C17H21NO5 |
| Molar mass | 319.357 g·mol−1 |
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Salicylmethylecgonine, (2′-Hydroxycocaine) is atropane derivative drug which is both a syntheticanalogue and a possible activemetabolite ofcocaine.[1] Its potencyin 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 higherLogP: 2.89 than that of cocaine: 2.62)[3] Note however that the compound2′-Acetoxycocaine would act as aprodrug 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 drop in potency. Salicylmethylecgonine also shows increased behavioral stimulation compared to cocaine similar to thephenyltropanes.[4] The hydroxy branch renders the molecule aQSAR 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.
| 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′-OHortho group of185d (i.e. salicylmethylecgonine), that intermolecular hydrogen bonding between its hydroxyortho 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 thepara-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 thep-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. Themeta-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]
