Synthesis and biological activity of 2-carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes.

Article Details

Citation

Meltzer PC, McPhee M, Madras BK

Synthesis and biological activity of 2-carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes.

Bioorg Med Chem Lett. 2003 Nov 17;13(22):4133-7.

PubMed ID
14592523 [ View in PubMed
]
Abstract

Cocaine inhibits the dopamine transporter and the consequent elevation of dopamine is thought to contribute to the addictive properties of cocaine. Tropane analogues of cocaine, targeted to the dopamine transporter (DAT), are a significant focus of drug design for cocaine addiction medications. Herein, we report the function of the ortho hydroxy substituents in dopamine with respect to the azabicyclo[3.2.1]octane skeleton. The introduction of the o-dihydroxyl functionality led to reduced binding potency at monoamine transporters, rather than enhanced interaction with the DAT. It is therefore likely that the binding site for these compounds on the DAT is not the same as that for dopamine. Notwithstanding the moderate potency of the free catechols (>100 nM), 7 manifested stimulant activity with a duration of effect that exceeded 4 h in a rat locomotor activity assay. Compound 10, a diacetoxy prodrug for 7, substituted fully for cocaine in a rat drug-discrimination paradigm and is now undergoing further investigation as a potential medication for cocaine abuse.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Dopamine5-hydroxytryptamine receptor 1AIC 50 (nM)>30000N/AN/ADetails
DopamineDopamine D2 receptorIC 50 (nM)460N/AN/ADetails
DopamineSodium-dependent dopamine transporterKi (nM)6400N/AN/ADetails
DopamineSodium-dependent serotonin transporterKi (nM)>1100000N/AN/ADetails