Salicylmethylecgonine, (2′-Hydroxycocaine) is a

tropane Tropane is a nitrogenous Bicyclic molecule, bicyclic organic compound. It is mainly known for the other alkaloids derived from it, which include atropine and cocaine, among others. Tropane alkaloids occur in plants of the families Erythroxylaceae ...

derivative drug which is both a synthetic analogue and a possible active

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

. Its potency ''in vitro'' is around 10x that of cocaine, 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) Note however that the compound 2′-Acetoxycocaine would act as a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

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 the

phenyltropane Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, the ...

s. 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. However, in overall binding affinity (not uptake inhibition) it displaces ligands better across the board than cocaine in all monoamine categories. Study of molecular modeling inferred that, in addition to int''ra''molecular hydrogen bonding between the adjacent 3''β''-carbonyl and the 2′-OH ''ortho'' group of 185d (''i.e.'' salicylmethylecgonine), that int''er''molecular 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.

References

{{Authority control Tropanes Dopamine reuptake inhibitors Stimulants Local anesthetics Salicylate esters Methyl esters 3-Hydroxypropenals

See also

References