Comparison of the enantiomers of (+/-)-doxanthrine, a high efficacy full dopamine D(1) receptor agonist, and a reversal of enantioselectivity at D(1) versus alpha(2C) adrenergic receptors. Eur Neuropsychopharmacol 2009 Feb;19(2):138-46
Date
11/26/2008Pubmed ID
19028082Pubmed Central ID
PMC2636714DOI
10.1016/j.euroneuro.2008.10.002Scopus ID
2-s2.0-57749201143 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
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.
Author List
Przybyla JA, Cueva JP, Chemel BR, Hsu KJ, Riese DJ 2nd, McCorvy JD, Chester JA, Nichols DE, Watts VJAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepineAdenylyl Cyclases
Animals
Cell Line
Cyclic AMP
Dopamine Agonists
Dose-Response Relationship, Drug
Humans
Male
Mice
Motor Activity
Neostriatum
Phenanthridines
Receptors, Adrenergic, alpha-2
Receptors, Dopamine D1
Stereoisomerism
Structure-Activity Relationship
Swine