Synthesis of tritium- and deuterium-labeled apomorphine

Ginos, James Z.; Lomonte, A.; Cotzias, George C.; Bose, Ajay K.; Brambilla, Raymond

doi:10.1021/ja00790a043

Cited by 25 publications

(7 citation statements)

References 3 publications

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“…Whole brain dopamine was determined fluorimetrically (16) in intact mice 30 min after the injection of either water or dopamine (17). Cerebral radioactivity was measured periodically on pairs of water-or nialamide-pretreated mice after injection of tritiated apomorphine (18). Statistical significance was determined with groups of at least six animals at the peak of behavioral effects coinciding with the peak of the radioactivity.…”

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confidence: 99%

Monoamine Oxidase and Cerebral Uptake of Dopaminergic Drugs

Cotzias¹,

Tang²,

Ginos³

1974

Proc. Natl. Acad. Sci. U.S.A.

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The brain uptake of amines that do not enter the brain or enter it poorly was promoted by noncompetitive inhibitors of monoamine oxidase, as shown by behavioral and chemical criteria. Mice pretreated with water or enzyme inhibitors other than those mentioned were placid after receiving dopamine (3,4-dihydroxyphenethylamine). Mice pretreated with monoamine oxidase inhibitors (nialamide or iproniazid) showed upon treatment with dopamine the brisk motor responses characteristic of treatment with its precursor, L-dopa (3,4-dihydroxyphenylalanine). After receiving dopamine, intact nialamide-pretreated mice showed marked increases of brain dopamine, in contrast to water-pretreated test mice or water-treated controls. In unilaterally caudectomized, nialamide-pretreated mice, dopamine induced marked lateral curving of the body toward the lesion followed by running in that direction. Noradrenaline or adrenaline induced curving in caudectomized mice, whereas intact ones remained placid.These catecholamines are bound and inactivated by monoamine oxidase. The cerebral uptakes of chemicals that are bound but not inactivated by monoamine oxidase were thereafter tested. Nialamide induced increased behavioral responses to apomorphine and to N-propyl noraporphine, increased cerebral concentrations of both, and a deep coloration of the brain from methylene blue (bound by monoamine oxidase) but not Evans blue (bound by albumin). Even large doses of nialamide, however, failed to affect the behavioral responses to oxotremorine, which has cholinergic rather than adrenergic or dopaminergic properties. Mitochondrial monoamine oxidase seems therefore to play a specific regulatory role in the transport of substances that it binds, either to inactivate or to release them.

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confidence: 99%

Monoamine Oxidase and Cerebral Uptake of Dopaminergic Drugs

Cotzias¹,

Tang²,

Ginos³

1974

Proc. Natl. Acad. Sci. U.S.A.

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“…Among the latter, N-n-propyl-n-butyldopamine (2) was the most potent DA receptor agonist2b and was further studied in animals as a potential anti-Parkinson drug. 4 The present study delineates further the dependence of dopaminergic effects on the structure of the N-substituents. Furthermore, the discovery that several of these , -disubstituted DA analogues possess dopaminergic activity suggests that one or several of these, given alone or in combination, may surpass the therapeutic value of presently available drugs.…”

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confidence: 57%

“…(2) Rotatory behavior of nigra-lesioned rats (Charles River, Sprague-Dawley male rats). These rats were injected with 6-hydroxydopamine stereotaxically in the right substantia nigra by the method of Ungerstedt et al 8 The operation was considered successful if 4 weeks following the lesion, injection of la…”

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confidence: 99%

New dopaminergic and potential anti-Parkinson compounds, N,N-disubstituted .beta.-(3,4-dihydroxyphenyl)ethylamines

Ginos¹,

Cotzias²,

Doroski³

1978

J. Med. Chem.

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Of the dopamine analogues synthesized and tested for dopaminergic agonism, the iV-n-propyl-N-substituted homologues induced strong postural asymmetric behavior indicative of dopaminergic action in caudectomized mice when injected intraperitoneally. IV-n-Propyl-IV-phenylethyl-, A-n-propyl-n-pentyl-(HI salt), and A-n-propyl-A-n-butyl-ß-(3,4-dihydroxyphenyl)ethylamine hydrochloride (2) (0.087 µ /g of body weight) ranked in decreasing order with respect to long-lasting effects in nigra-lesioned rats. In contrast, neither the N-monosubstituted nor the IV,IV-dialkyl analogues possessing identical A-alkyl groups showed dopaminergic effects while the A-methyl-N-substituted analogues demonstrated little or no effect. Analogues with branching IV-alkyl substituents (IV-methyl-IV-isobutyl and Nn-propyl-IV-isobutyl) showed also dopaminergic effects. In contrast to 2, IV-n-propyl-IV-n-butyl-d-(3,4-methylenedioxyphenyl)ethylamine hydrochloride failed to elicit any behavioral effects when tested similarly. The results suggest that the nitrogen substituents may play also an important role in binding to the receptor site by possibly interacting with its hydrophobic regions. Furthermore, in contrast to currently used dopamine agonists in the treatment of parkinsonism, , -disubstituted dopamine analogues can be easily and inexpensively synthesized with a spectrum ranging from short to prolonged dopaminergic effects. In accordance with current trends, one or more of these agonists could be used either alone or in combination with L-Dopa, as required by each patient, to optimize the treatment of Parkinson's disease.The two aporphines, apomorphine (la) and N-npropylnorapormorphine (lb), alleviate the symptoms of

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“…Similarities in the sign and magnitude of ketone Cotton effects indicated that I possessed the same trans-fused cyclopentanone ring system (C-la, C-SP-CH20) as 11. 13 were changed by the conditions of the NMR instrument 1!XL-100), as shown in the data. In addition, Samek's rule (11) (J7.…”

Section: Resultsmentioning

confidence: 99%

“…Early studies on the deuteration of I gave conflicting evidence on the site and extent of deuteration (13) or provided methodology requiring total synthesis of the aporphine skeleton (14). One report (13) suggested that deuterated analogs of I would not be suitable for use in a mass spectral assay due to proton scrambling during vaporization.…”

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confidence: 99%