Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol.
Ethanol elevates methylphenidate (1) plasma concentrations and yields the metabolite ethylphenidate (2). The therapeutic implications are under investigation. The IC(50) for dopamine reuptake inhibition by (+)-2 was 27 nM compared to 367 nM for cocaine and 1730 nM for (-)-2. Binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-2 than for cocaine. Intraperitoneal (+)-2 was approximately half as active as (+)-1 in stimulating mouse motor activity at 5 mg/kg, but (+)-2 was as active as (+)-1 at 10 mg/kg.
Patrick
Kennerly S
KS
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. patrickk@musc.edu
Williard
Robin L
RL
VanWert
Adam L
AL
Dowd
Justin J
JJ
Oatis
John E
JE
Middaugh
Lawrence D
LD
D000818:Animals; D002460:Cell Line; D003042:Cocaine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004951:Esterification; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011485:Protein Binding; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C493227:SLC6A2 protein, human; C493228:Slc6a2 protein, mouse; D027981:Symporters; D008774:Methylphenidate; D000431:Ethanol; C042400:ethylphenidate; D003042:Cocaine