Parkinson’s disease is a neurodegenerative condition involving the death of dopaminergic neurons in the substantia nigra. Dopamine D1 receptor agonists are potential alternative treatments to current therapies that employ L-DOPA, a dopamine precursor. We evaluated the pharmacological profiles of the enantiomers of a novel dopamine D1 receptor full agonist, doxanthrine (DOX) at D1 and α2C adrenergic receptors. (+)-DOX displayed greater potency and intrinsic activity than (-)-DOX in porcine striatal tissue and in a heterologous D1 receptor expression system. Studies in MCF7 cells, which express an endogenous human dopamine D1-like receptor, revealed that (-)-DOX was a weak partial agonist/antagonist that reduced the functional activity of (+)-DOX and dopamine. Surprisingly, (-)-DOX had 10-fold greater potency than (+)-DOX at α2C adrenergic receptors, with an EC50 value of 4 nM. These findings demonstrate a reversed stereoselectivity for the enantiomers of DOX at D1 and α2C receptors and have implications for the therapeutic utility of doxanthrine.


This is the author accepted manuscript of Comparison of the enantiomers of (±)-doxanthrine, a high efficacy full dopamine D1 receptor agonist, and a reversal of enantioselectivity at D1 versus alpha2C adrenergic receptors. European Neuropsychopharmacology. 2009. The published version can be found at http://www.europeanneuropsychopharmacology.com/article/S0924-977X(08)00270-8/abstract.


Dopamine D1 receptors, adrenergic receptors, Parkinson’s disease, enantiomeric drugs, intrinsic activity, locomotor activity

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