Asymmetric synthesis and pharmacology of methylphenidate and its para-substituted derivatives.
We report the first asymmetric synthesis of the individual enantiomers of methylphenidate (1). From d-pipecolic acid, the (2R,2'R) and (2S,2'R) enantiomers of 1 were obtained in > 99% optical purity while the (2S,2'S) and (2R,2'S) enantiomers of 1 were derived from l-pipecolic acid in 96% optical purity. The versatility of this methodology is demonstrated with the synthesis of the (2R,2'R) and (2S,2'S) enantiomers of p-bromo and p-methoxy derivatives in similar yields and enantiomeric purities. Comparative neurochemical assessments of these synthesized enantiomers at purported dopamine, norepinephrine, and serotonin uptake sites along with locomotor activity studies in rats are also reported.
Thai
D L
DL
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
Sapko
M T
MT
Reiter
C T
CT
Bierer
D E
DE
Perel
J M
JM
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D007202:Indicators and Reagents; D007536:Isomerism; D007700:Kinetics; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D007202:Indicators and Reagents; D008774:Methylphenidate; D004298:Dopamine; D009638:Norepinephrine