- Mass spectrometric studies of cocaine disposition in animals and humans using stable isotope-labeled analogues
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Ion cluster technique in conjunction with gas chromatography-mass spectrometry (GC-MS) was used for the identification and quantitation of major metabolites of cocaine (1a) in rat and humans. In a typical experiment, a female rat weighing 250 gm was intraperitoneally administered a 20-mg/kg mixture of 1a, NCD3-cocaine (1b), OCD3-cocaine (1c), and 4T2-cocaine (1d). The urine was collected, extracted with organic solvents, and separated into several fractions using TLC and HPLC techniques. Tritium radioactivity in a metabolically stable position in 1d was useful in the separation of metabolites, while the deuterium labeled 1(b+c), creating an artificial isotopic cluster, provided specific identification of metabolites by mass spectrometric interpretation. Norcocaine (2), benzoylnorecgonine (3), N-hydroxynorcocaine (4), methylecgonidine (5), benzoylecgonine (11), ecgonine methyl ester (9), hydroxycocaine (7), hydroxymethoxycocaine (10), and dimethoxyhydroxycocaine (6) were found to be the major metabolites of 1a in the rat urine as well as in plasma. The whole brain analysis showed significant amounts of unmetabolized 1a and 2, and minor concentrations of 9, 5, 7, and 10, and traces of 6. Some of these metabolites have been reported earlier by us as well as other investigators and are unequivocally confirmed in this work. Unmetabolized 1a, its pharmacologically active metabolite 2, and other major metabolites were quantitated in the rat brain, plasma, and urine using stable isotope-labeled analogues as internal standards and selected ion monitoring (SIM) mass spectrometry. The pharmacokinetic profiles of 1a and 2 indicate half-lives of 20 min in the brain and plasma. These data are in good agreement with widely reported short-lived behavioral effects of cocaine. The ion cluster methodology developed for the animal studies was successfully used in the identification of metabolic pathways of cocaine in humans. Several human urine samples were analyzed using GC-MS and SIM procedures, and the metabolic profile in humans was found to be similar to the one in rat.
- Jindal,Lutz
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- The synthesis of deuterium-labelled cocaine, cocaethylene and metabolites
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We describe the syntheses of benzoylecgonine (1,1,1-2H3)methyl ester [(2H3) cocaine], (2H5)benzoylecgonine, (2H5)benzoylecgonine methyl ester [(2H5/su
- Everhart, E. Thomas,Jacob III, Peyton,Mendelson, John,Jones, Reese T.
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p. 1265 - 1275
(2007/10/03)
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- Cocaine and 3β-(4'-substituted phenyl)tropane-2β-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter
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Several 2β-carboxylic acid ester and amide analogues of cocaine and of 3β-(4'-substituted phenyl)tropane-2β-carboxylic acid were prepared. The binding affinities of these compounds, and of some previously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters of 3β-(4'-methylphenyl)and 3β-(4'-chlorophenyl)tropane-2β-carboxylic acid are highly potent and highly selective for the DA transporter. The isopropyl esters of 3β-(4'- chlorophenyl)- and 3β-(4'-iodophenyl)tropane-2β-carboxylic acid also possess high DA affinity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selective for the DA transporter than cocaine. Tertiary amide analogues of cocaine and of 3β-(4'-substituted phenyl)tropane-2β-carboxylic acids are more potent inhibitors of radioligand binding at the DA transporter than the primary and secondary amide analogues. In particular, 3β-(4'- chlorophenyl)tropane-2β-N-morpholinocarboxamide as well as the 3β-(4'- chlorophenyl)- and 3β-(4'-iodophenyl)tropane-2β-N-pyrrolidinocarboxamides possess high affinity and selectivity for the DA transporter. The N,N- dimethylamide cocaine analogue is the most selective cocaine amide derivative for the DA transporter. High correlation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selected group of analogues. Within this group, one compound, the isopropyl ester of 3β-(4'-iodophenyl)-tropane-2β- carboxylic acid, was found to be more potent in the inhibition of radioligand binding than in the inhibition of DA uptake. Taken together with its high potency and selectivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.
- Carroll,Kotian,Dehghani,Gray,Kuzemko,Parham,Abraham,Lewin,Boja,Kuhar
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p. 379 - 388
(2007/10/02)
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- 2β-Substituted Analogues of Cocaine. Synthesis and Inhibition of Binding to the Cocaine Receptor
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The potencies of a series of 2β-substituted cocaine analogues to displace -3β-(p-fluorophenyl)tropane-2β-carboxylic acid methyl ester binding in rat striatal membranes demonstrate the requirement for a 2β-substituent with two hydrogen-bond acceptors.The insensitivity of the ester moiety to steric and electronic factors suggests its modification to provide site-specific irreversible ligands.
- Lewin, Anita H.,Gao, Yigong,Abraham, Philip,Boja, John W.,Kuhar, Michael J.,Carroll, F. Ivy
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p. 135 - 140
(2007/10/02)
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