Mechanism of Action
Bupropion is a dopamine and norepinephrine reuptake inhibitor and releaser. It is about twice as potent an inhibitor of dopamine reuptake than of norepinephrine reuptake. Besides reuptake inhibition of dopamine and norepinephrine, bupropion also causes the release of dopamine and norepinephrine. As bupropion is rapidly converted in the body into several metabolites with differing activity, its action cannot be understood without reference to its metabolism. The occupancy of dopamine transporter (DAT) by bupropion and its metabolites in the human brain as measured by positron emission tomography was 6–22% in an independent study and 12–35% according to GlaxoSmithKline researchers. Based on analogy with serotonin reuptake inhibitors, higher than 50% inhibition of DAT would be needed for the dopamine reuptake mechanism to be a major mechanism of the drug's action. By contrast, approximately 65% occupancy or greater of DAT is required to achieve euphoria and reach abuse potential. However recent research indicates that dopamine is inactivated by norepinephrine reuptake in the frontal cortex, which largely lacks dopamine transporters, therefore bupropion can increase dopamine neurotransmission in this part of the brain, and this may be one possible explanation for any additional dopaminergic effects. Bupropion does not inhibit monoamine oxidase or serotonin reuptake. However, it has been shown to indirectly enhance the firing of serotonergic neurons, via activation of downstream norepinephrine flow. Bupropion has also been shown to act as a noncompetitive nicotinic antagonist. The degree of inhibition of α3β4 receptors correlates well with the decrease in self-administration of morphine and methamphetamine in rats, and may be relevant to the effect of bupropion on nicotine addiction. The drug is supplied as a racemic mixture, and the activities of the individual enantiomers were not found to differ.
Two SAR studies date from 2009 and 2010.
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