Centrally acting emetics. 5. Preparation and pharmacology of 10-hydroxy-11-methoxyaporphine (Isoapocodeine). In vitro enzymic methylation of apomorphine

Cannon, Joseph G.; Smith, Rebekah E.; Modiri, Ali-Reza; Sood, S; Borgman, Robert J.; Aleem, Mohd; Long, J P

doi:10.1021/jm00273a016

Cited by 55 publications

(12 citation statements)

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“…In rats, the major part of apomorphine undergoes hepatic metabolism by O ‐glucuronidation and is then eliminated as glucuronides in the urine 20, 21. However, in vitro studies suggest that apomorphine may also be methylated by the enzyme COMT,22–25 largely present in the liver, with production of 10 methoxy‐apomorphine or apocodeine 26. A recent study has shown that tolcapone, a central and peripheral COMT inhibitor, can increase the apomorphine bioavailability by reducing its liver catabolism in Sprague–Dawley rats 27.…”

Section: Discussionmentioning

confidence: 99%

Safety of entacapone and apomorphine coadministration in levodopa‐treated Parkinson's disease patients: Pharmacokinetic and pharmacodynamic results of a multicenter, double‐blind, placebo‐controlled, cross‐over study

Zijlmans

Debilly²,

Rascol

et al. 2004

Movement Disorders

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We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three-sequence, three-period, crossover design. Patients were randomly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at baseline and study end. Pharmacokinetic parameters for apomorphine (C(max), AUC, t(max), t(1/2)) were unchanged by the administration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkinson's disease.

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Section: Discussionmentioning

confidence: 99%

Safety of entacapone and apomorphine coadministration in levodopa‐treated Parkinson's disease patients: Pharmacokinetic and pharmacodynamic results of a multicenter, double‐blind, placebo‐controlled, cross‐over study

Zijlmans

Debilly²,

Rascol

et al. 2004

Movement Disorders

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“…oquinoline ring still predominated. The DA agonist, apomorphine, which structurally contains an unsubstituted TIQ ring separate from an extended DA molecule, apparently is mono-0-methylated in vitro almost entirely on the original p-hydroxyl group to form apocodeine (Cannon et al, 1972), but apomorphine is not an endogenous CA derivative. Interestingly, another DA receptor agent, 2-amino-6,7-dihydroxytetralin (ADTN), which also has an internal extended DA, is reported to be metabolized mainly to an 0-methylated isomer involving the original rn-hydroxyl group, following administration of its o-dibenzoyl ester to rats (Rollema et al, 1980).…”

Section: Discussionmentioning

confidence: 99%

Catecholamine‐Derived Tetrahydroisoquinolines: O‐Methylation Patterns and Regional Brain Distribution Following Intraventricular Administration in Rats

Collins

Origitano

1983

Journal of Neurochemistry

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The metabolism of 6,7-dihydroxy (catecholic)-1,2,3,4-tetrahydroisoquinolines (TIQs) is of interest because the heterocyclic substances may form in mammals normally or during certain disease via condensations of catecholamines (CAs) with aldehydes or alpha-keto acids. With a specific capillary gas chromatography procedure and confirmatory liquid chromatographic assays, we have determined the structural isomers and relative amounts of mono-O-methylated (phenolic) TIQ metabolites in several rat brain regions 40 min following the acute intracerebroventricular injection of four structurally related catecholic TIQs. In sharp contrast with the established selective m-O-methylation of dopamine (DA) by catechol-O-methyltransferase in brain, the two simple TIQs derived from DA produced predominantly or even exclusively the metabolic isomer arising from methylation of the original p-hydroxyl group (7-O-methylation). In three catecholaminergic brain regions examined, the 7-O-methyl isomer was the only detectable phenolic metabolite of (+/-) salsolinol-1-carboxylic acid (a condensation product of DA and pyruvic acid) and, as first noted by Bail et al. (1980), constituted 95% of the two possible isomeric mono-O-methyl metabolites of (+/-) salsolinol (TIQ derivative of DA and acetaldehyde). Though less, the 7-O-methyl isomers still were a significant proportion (40-55%) of the two mono-O-methylated metabolites of (+/-) 4-hydroxy-desmethylsalsolinol (a TIQ derived from norepinephrine and formaldehyde), or of the DOPA/acetaldehyde-derived TIQ, (cis) salsolinol-3-carboxylic acid. In the time frame of the study, all four administered TIQs showed higher levels in hypothalamus than in striatum or hippocampus, with the two carboxylated alkaloids displaying the greatest differences.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…HCl 1/2H20 (Merck) according to literature procedures (7). Boldine (GC internal standard) was purchased from Nutritional Biochemicals Corp. Each compound melted according to literature values (7) and was homogeneous by rhm-layer chromatography and GC. Ascorbic acid and dithiothreitol were purchased from Sigma Chemical Co.; sodium bisulfite was obtained from Fisher Scientific Co.…”

Section: Methodsmentioning

confidence: 99%

“…Recent interest in apomorphine (compound 1) stems from its usefulness in the experimental treatment of Parkinson's disease (9) and a number of other disorders (3,4). In mammalian systems, apomorphine undergoes methylation (7) and glucuronidation (15) primarily at the 10position. A rat liver catechol O-methyltransferase preparation produced a mixture of the 10methylated product, apocodeine (compound 2), and its l1-methylated isomer, isoapocodeine (compound 3), in a ratio of 81:1 (7).…”

mentioning

confidence: 99%

“…In mammalian systems, apomorphine undergoes methylation (7) and glucuronidation (15) primarily at the 10position. A rat liver catechol O-methyltransferase preparation produced a mixture of the 10methylated product, apocodeine (compound 2), and its l1-methylated isomer, isoapocodeine (compound 3), in a ratio of 81:1 (7). Whereas apocodeine (compound 2) can be conveniently prepared by the monomethylation of compound 1 (7) or by chemical O-demethylation of 10,11dimethoxyaporphine (compound 4) (1), the isomeric phenol, compound 3, is much more difficult to obtain.…”

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confidence: 99%

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Regiospecific synthesis of isoapocodeine from 10,11-dimethoxyaporphine by using Cunninghamella elegans

Smith¹,

Davis²

1978

Appl Environ Microbiol

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Centrally acting emetics. 5. Preparation and pharmacology of 10-hydroxy-11-methoxyaporphine (Isoapocodeine). In vitro enzymic methylation of apomorphine

Cited by 55 publications

References 7 publications

Safety of entacapone and apomorphine coadministration in levodopa‐treated Parkinson's disease patients: Pharmacokinetic and pharmacodynamic results of a multicenter, double‐blind, placebo‐controlled, cross‐over study

Safety of entacapone and apomorphine coadministration in levodopa‐treated Parkinson's disease patients: Pharmacokinetic and pharmacodynamic results of a multicenter, double‐blind, placebo‐controlled, cross‐over study

Catecholamine‐Derived Tetrahydroisoquinolines: O‐Methylation Patterns and Regional Brain Distribution Following Intraventricular Administration in Rats

Regiospecific synthesis of isoapocodeine from 10,11-dimethoxyaporphine by using Cunninghamella elegans

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