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.
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.
Przybyla
Julie A
JA
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Cueva
Juan P
JP
Chemel
Benjamin R
BR
Hsu
K Joseph
KJ
Riese
David J
DJ
McCorvy
John D
JD
Chester
Julia A
JA
Nichols
David E
DE
Watts
Val J
VJ
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis / Q000235:genetics; D018491:Dopamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
C516224:2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno(3,4-c)isoquinoline; C547774:ADRA2C protein, human; C547775:Adra2c protein, mouse; D018491:Dopamine Agonists; D010617:Phenanthridines; D018341:Receptors, Adrenergic, alpha-2; D017447:Receptors, Dopamine D1; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases