Methylphenidate - Pharmacology

Pharmacology

Methylphenidate is a piperidine derivative that primarily acts as a norepinephrine-dopamine reuptake inhibitor. Methylphenidate is most active at modulating levels of dopamine and to a lesser extent noradrenaline. Similar to amphetamines and cocaine, key targets of methylphenidate are the dopamine transporter (DAT) and noradrenaline transporter (NET). MPH binds to and blocks DAT and NET, inhibiting the transport of the transporters' respective substrates. Moreover, MPH is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamines. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from amphetamines, as methylphenidate is thought to increase general firing rate, whereas amphetamines reverse the flow of the monoamine transporters. Although methylphenidate can be considered an amphetamine derivative, subtle differences exist in its pharmacology; amphetamine works as a dopamine transport substrate whereas methylphenidate works as a dopamine transport blocker.

Methylphenidate has both DAT and NET binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextro- and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT_1A and 5HT_2B subtypes, though direct binding to the serotonin transporter was not observed.

The enantiomers and the relative psychoactive effects and CNS stimulation of dextro- and levo-methylphenidate is analogous to what is found in amphetamine, where dextro-amphetamine is considered to have a greater psychoactive and CNS stimulatory effect than levo-amphetamine.