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Rapid Stereoselective Hydrolysis of (+)‐Cocaine in Baboon Plasma Prevents Its Uptake in the Brain: Implications for Behavioral Studies
Author(s) -
Gatley S. J.,
MacGregor R. R.,
Fowler J. S.,
Wolf A. P.,
Dewey S. L.,
Schlyer D. J.
Publication year - 1990
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1990.tb01933.x
Subject(s) - baboon , chemistry , butyrylcholinesterase , pharmacology , alkaloid , physostigmine , stereoselectivity , human brain , metabolism , stereochemistry , biochemistry , acetylcholinesterase , medicine , enzyme , aché , psychology , neuroscience , catalysis , acetylcholine
The naturally occurring enantiomer of cocaine, (–)‐cocaine, has been previously labeled with 11 C on the N ‐methyl group and used in conjunction with positron emission tomography to show that cocaine is rapidly taken up in the striata of human and baboon brain. In the present study, the behaviorally inactive (+)‐cocaine was similarly labeled, with a view to its use for measuring the nonspecific binding of cocaine. No brain uptake was seen, although transport of cocaine into the brain is not expected to be stereoselective. The explanation for the lack of uptake was determined to be very rapid metabolism of (+)‐cocaine in the blood. By 30s after administration of labeled (+)‐cocaine, it was undetectable in plasma. In vitro studies demonstrated that (+)‐cocaine is 50% debenzoylated to (+)‐ecgonine methyl ester within 5 s of exposure to baboon plasma but not to washed erythrocytes. The hydrolysis of (–)‐cocaine is at least 1,000 times slower. Serum butyrylcholinesterase (EC 3.1.1.8) appears to be responsible for this hydrolysis, as evidenced by its inhibition by physostigmine and catalysis by commercially available pseudocholinesterase from horse and human blood.