Binding of dopamine and 3-methoxytyramine as l-DOPA metabolites to human α2-adrenergic and dopaminergic receptors

The ability of l-3,4-dihydroxyphenylalanine (l-DOPA), l-DOPA-methyl ester and their major metabolites, dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic (HVA), 3-O-methyldopa and 3-methoxytyramine (3-MT) to bind to α2 adrenergic and D1 and D2 dopamine receptors was assessed by radioligand binding to cloned human receptors expressed in cell lines. As anticipated, dopamine bound with high affinity to D1 (IC50 1.1 ± 0.16 μM) and D2 (IC50 0.7 ± 0.3 μM) dopamine receptors. However, dopamine also bound with high affinity to α2A (IC50 was 2.6 ± 0.5 μM), α2C (IC50 3.2 ± 0.7 μM). 3-MT bound to α2A with high affinity (IC50, 3.6 ± 0.2 μM) though moderate affinity to α2c, D1 and D2 receptors (values of IC50 were 55 ± 14, 121 ± 43, 36 ± 14 μM, respectively). l-DOPA-methyl ester bound with high affinity to α2 (IC50 17–36 μM) but not dopamine receptors (IC50 0.9–2.5 mM). l-DOPA, 3-O-methyldopa and DOPAC had no observable effect on binding to any of the receptors tested. These data suggest that the effects of l-DOPA in Parkinson's disease may result from actions of its metabolites dopamine and 3-MT on both dopaminergic and non-dopaminergic receptors. These findings may provide explanations for the differences between l-DOPA and dopamine receptor agonists in mediating anti-parkinsonian effects and propensity to be associated with dyskinesia and motor complications such as wearing-off and on-off.