Biological Effects of Cocaine Derivatives I: Improved Synthesis and Pharmacological Evaluation of Norcocaine

Borne, Ronald F.; Bedford, John A.; Buelke, Judith L.; Craig, Cathy B.; Hardin, Thomas C.; Kibbe, Arthur H.; Wilson, Marvin C.

doi:10.1002/jps.2600660133

Cited by 41 publications

(2 citation statements)

References 9 publications

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“…Norcocaine and N-OH norcocaine were synthesized according to the methods of Borne et al [11] and Misra et al [12]. Potassium phosphate was from Mallinckrodt, and all other chemicals were reagent grade or better and purchased from Fisher unless otherwise noted.…”

Section: Methodsmentioning

confidence: 99%

Subacute Cocaine Treatment Changes Expression of Mouse Liver Cytochrome P450 Isoforms

Powers

Shuster²

1999

Pharmacology

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Acute administration of single high doses of cocaine (50 or 60 mg/kg) produces liver injury in mice that have been pretreated with inducers of mixed function oxidases. Multiple low doses of cocaine (10–30 mg/kg) will produce hepatotoxicity without prior induction. To establish whether cocaine can induce its own activation, mice were given three daily injections of cocaine. Total cytochrome P450 content of the liver did not change. After 3 days the amount of cytochrome P450 2B10, as measured by pentoxy resorufin-O-dealkylase activity and immunoblotting, increased 3-fold. Cytochrome P450 2A5-catalyzed coumarin 7-hydroxylase activity and immunoreactive protein increased by about 50%. Enzyme activities and Western blotting of isoforms 1A, 2E, and 3A showed no change during this time. Chronic cocaine increased N-hydroxylation of norcocaine. Immunoinhibition studies showed that cytochrome P450 2A5 was the major isoform responsible for norcocaine N-hydroxylation. These results demonstrate that chronic cocaine can induce its own metabolism. Similar increases were also observed in mice not susceptible to liver injury from chronic cocaine.

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Section: Methodsmentioning

confidence: 99%

Subacute Cocaine Treatment Changes Expression of Mouse Liver Cytochrome P450 Isoforms

Powers

Shuster²

1999

Pharmacology

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“…However, unlike cocaine, the WIN compounds are weak local anaesthetics (Clarke et al, 1973). Norcocaine, a N-demethylated metabolite of cocaine, has a pharmacological profile similar to cocaine and has been found to show effects ranging from equipotency to three times the potency of cocaine (Misra, Pontani & Mule 1976b;Borne, Bed-ford, Buelke, Craig, Hardin, Kibbe & Wilson, 1977;McKenna, Ho & Englert, 1979;Spealman et aL, 1979).…”

Section: Introductionmentioning

confidence: 99%

Cocaine Cue in Pigeons: Time Course Studies and Generalization to Structurally Related Compounds (Norcocaine, Win 35,428 and 35,065‐2) and (+)‐amphetamine

Järbe

1981

British J Pharmacology

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1 Pigeons trained to discriminate between the presence or absence of effects induced by cocaine hydrochloride (5.6 mg/kg) were tested for generalization with norcocaine and two phenyltropane analogues (WIN 35,428 and WIN 35,. Separate dose-effect curves were obtained at different intervals after the injections so that possible changes both in potency and duration of action could be evaluated.2 Results showed that all of these drugs fully generalized to cocaine. The order of potency was WIN 35,428 > norcocaine > WIN 35,065-2 > cocaine when tested either at 15 or 60 min after injection. The cocaine-like effects were strongest for all drugs when tested 15 min after injection as compared to the tests at the 60 min interval. The decay of the cocaine-like stimulus effects occurred at about the same rate.3 Apomorphine (0.3, 0.56 and 1 mg/kg), morphine (3 and 5.6 mg/kg), A9-tetrahydrocannabinol (0.3 and 0.56 mg/kg), and lysergic acid diethylamide (LSD-25, 0.056 and 0.1 mg/kg) did not induce more than 30% cocaine appropriate responses. (+)-Amphetamine produced 73% and 85% cocaine appropriate responses depending on the injection-test interval used, 15 and 30 min respectively. 4 The amphetamine homologue, para-hydroxyamphetamine (3.8 mg/kg) did not generalize to cocaine. Tests with 30 mg/kg of procaine produced 40% cocaine appropriate responses. Cocaine is effective also when administered by gavage into the opening of the proventriculus. 5 The use of the drug discrimination technique for studying structure activity relationships of drugs is discussed.

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Mass spectrometric determination of cocaine and its biologically active metabolite, norcocaine, in human urine

Jindal

Lutz

Vestergaard

1978

Biol. Mass Spectrom.

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A gas chromatographic mass spectrometric assay has been developed for the determination of cocaine and its pharmacologically active metabolite, norcocaine, in human urine. [2H3]Cocaine and [2H3]norcocaine were used as internal standards. The assay utilizes selective focusing to monitor in a gas chromatographic effluent the molecular ions of cocaine, [2H3]cocaine and the fragment ions of trifluoroacetylated norcocaine, [2H3]norcocaine generated by electron impact ionization. The assay can measure 2 ng ml-1 each of cocaine and norcocaine with about 5% precision. The curves, relating the amounts of cocaine and norcocaine added to control urine per 'fixed' amounts of their labeled analogs, versus the appropriate ion intensity ratios are straight lines with nearly zero intercepts and slopes of 0.98 +/- 0.01 and 0.98 +/- 0.02, respectively. The methodology is used for the analysis of urinary cocaine and norcocaine from three human subjects who received 100 mg cocaine-HCL intravenously.

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Biological Effects of Cocaine Derivatives I: Improved Synthesis and Pharmacological Evaluation of Norcocaine

Cited by 41 publications

References 9 publications

Subacute Cocaine Treatment Changes Expression of Mouse Liver Cytochrome P450 Isoforms

Subacute Cocaine Treatment Changes Expression of Mouse Liver Cytochrome P450 Isoforms

Cocaine Cue in Pigeons: Time Course Studies and Generalization to Structurally Related Compounds (Norcocaine, Win 35,428 and 35,065‐2) and (+)‐amphetamine

Mass spectrometric determination of cocaine and its biologically active metabolite, norcocaine, in human urine

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