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

被引:14
作者
Przybyla, Julie A. [1 ]
Cueva, Juan P. [1 ]
Chemel, Benjamin R. [1 ]
Hsu, K. Joseph [1 ]
Riese, David J., II [1 ]
McCorvy, John D. [1 ]
Chester, Julia A. [2 ]
Nichols, David E. [1 ]
Watts, Val J. [1 ]
机构
[1] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA
[2] Purdue Univ, Dept Psychol Sci, W Lafayette, IN 47907 USA
关键词
Dopamine D-1 receptors; Adrenergic receptors; Parkinson's disease; Enantiomeric drugs; Intrinsic activity; Locomotor activity; PARKINSONS-DISEASE; AGED MONKEYS; WORKING-MEMORY; DIHYDREXIDINE; SKF-38393; MICE; SENSITIZATION; PERFORMANCE; INDUCTION; LEVODOPA;
D O I
10.1016/j.euroneuro.2008.10.002
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:138 / 146
页数:9
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