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

Parkinson's disease is a neurodegenerative condition involving the death of dopaminergic neurons in the substantia nigra. Dopamine D-1 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 D-1 receptor full agonist, doxanthrine (DOX) at D-1 and (alpha(2C) adrenergic receptors. (+)-DOX displayed greater potency and intrinsic activity than (-)-DOX in porcine striatal tissue and in a heterologous D-1 receptor expression system. Studies in MCF7 cells, which express an endogenous human dopamine D-1-like receptor, revealed that (-)-DOX was a weak partial agonist/antagonist that reduced the functional activity of (+)-DOX and dopamine. (-)-DOX had 10-fold greater potency than (+)-DOX at alpha(2C) adrenergic receptors, with an EC50 value of 4 nM. These findings demonstrate a reversed stereoselectivity for the enantiomers of DOX at D-1 and alpha(2C) receptors and have implications for the therapeutic utility of doxanthrine. (C) 2008 Elsevier B.V. and ECNP. All rights reserved.