Relation between the structure of certain methoxyphenylethylaminederivatives and the occurrence of a Hypokinetic Rigid Syndrome

Ernst, A. M.

doi:10.1007/bf00402360

Cited by 54 publications

(10 citation statements)

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“…The compounds tested were apomorphine, which simulates the action of dopamine (see, for example, Ernst, 1965) and methysergide (see, for example, Woodruff, Walker & Kerkut, 1971) and ergometrine (see, for example, Ascher, 1972) which are inhibitors. As Fig.…”

Section: Hyperpolarization Receptorsmentioning

confidence: 99%

On the receptors which mediate the hyperpolarization of salivary gland cells of Nauphoeta cinerea Olivier.

Ginsborg¹,

House²,

Silinsky³

1976

The Journal of Physiology

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SUMMARY1. The actions of sympathomimetics and of catecholamine antagonists have been investigated on the membrane potential and responses to nerve stimulation of acinar cells of the salivary gland of Nauphoeta cinerea Olivier.2. Hyperpolarizations such as those evoked by nerve stimulation and by low concentrations of adrenaline, noradrenaline and dopamine were not produced by the a-agonists amidephrine and methoxamine. Isoprenaline was active, but only in concentrations above 100 /M.3. Tyramine, an indirectly acting sympathomimetic, and high concentrations of methoxamine caused an increase in the rate of the small transient hyperpolarizations sometimes seen in the absence of stimulation.4. The response to nerve stimulation was unaffected by propranolol (20 1M), an c-adrenergic antagonist. Phentolamine, an a-adrenergic antagonist, reduced matching responses to nerve stimulation and to dopamine to about the same extent. 5. As on other systems responsive to low concentrations of dopamine, apQmorphine was active, although only in high concentration, and ergometrine and methysergide were antagonistic both to nerve stimulation and to dopamine.

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Section: Hyperpolarization Receptorsmentioning

confidence: 99%

On the receptors which mediate the hyperpolarization of salivary gland cells of Nauphoeta cinerea Olivier.

Ginsborg¹,

House²,

Silinsky³

1976

The Journal of Physiology

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“…On the assumption that the present results are relevant to the central nervous system, it is of interest to consider their possible bearing on the theories which attribute certain psychoses to abnormal metabolites (see e.g. Ernst, 1965) which over-stimulate dopaminergic systems (see e.g. Snyder et al, 1974;Matthysse & Lipinski, 1975).…”

Section: Discussionmentioning

confidence: 99%

On the Actions of Compounds Related to Dopamine at a Neurosecretory Synapse

Ginsborg

Turnbull

House

1976

British J Pharmacology

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Royal (Dick) School of Veterinary Studies, Summerhall, Edinburgh EH9 1 QH I The effects of a number of substances related to dopamine, including all its methylated derivatives, were investigated on the membrane potential and response to nerve stimulation of cockroach salivary gland cells. 2 Only N-methyldopamine (epinine), N,N-dimethyldopamine and N,N-dimethylnoradrenaline, all with unsubstituted hydroxyl groups, directly resembled dopamine in producing a hyperpolarization which could be as large as that caused by maximal nerve stimulation. During the continued presence of these substances the hyperpolarization waned and responses to nerve stimulation declined. 3 Many of the compounds caused one or both of two other effects, namely an increase in the rate of 'spontaneous miniature hyperpolarizations' and an enhancement of the submaximal responses to single nerve stimuli. There were no obvious structural requirements for these effects.

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“…Indeed, both DMPEA and its N-acetyl derivative NADMPEA are known to produce behavioural changes in animals, the latter being the more potent (Bindler, Sanghvi & Gershon, 1968;Friedhoff & Schweitzer, 1968). Although these compounds possess the 4-methoxy group necessary for psychotomimetic activity, neither DMPEA nor NADMPEA produce the hallucigenic effects of the structurally similar mescaline when administered orally to man.In addition, reports claiming that DMPEA is present in parkinsonian urine have been supported by Ernst (1965), Barbeau, Tetreault & others (1966) and Shulgin, Sargent & Naranjo (1969) who showed in animal studies, used as a model for parkinsonism, that DMPEA, 3-hydroxy-4-methoxyphenethylamine (3HMPEA) and mescaline produced the characteristic akinesia in rats.A recent report by Barrass, Coult & Pinder (1972) showed that 3HMPEA but not the isomeric 4HMPEA nor DMPEA itself increased dopamine oxidation and inhibited 5-hydroxytryptamine (5-HT) oxidation in vitro. It was suggested, therefore, that 3HMPEA could be the endogenous toxin in parkinsonism producing akinesia and causing an imbalance in the dopamine: 5-HT ratio.…”

mentioning

confidence: 93%

“…Pharmac., 1973, 25,416 Treatment with L-dopa is reported to produce psychotomimetic side-effects (Jenkins & Schweiger, 1971). In schizophrenia, the high dopamine levels in the extrapyramidal system could produce sufficiently high levels of DMPEA for hallucigenic activity and at the same time antagonize the akinetic effects as seen in animal studies (Ernst, 1965). This is supported by the fact that neuroleptic drugs used in the treatment of schizophrenia, effectively reduce dopamine levels by increasing its turnover rate and are well known to produce a parkinsonian syndrome as a side-effect (Ayd, 1961).…”

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Abnormal O-methylated dopamine metabolites: The endogenous toxins of schizophrenia or parkinsonism?

Smith

Hartley

1973

Journal of Pharmacy and Pharmacology

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Abnormal O-methylated dopamine metabolites: the endogenous toxins of schizophrenia or parkinsonism? 415 In spite of much work that would suggest the involvement of 3,4-dimethoxyphenethylamine (DMPEA) and its derivatives in either schizophrenia (Takesada, Kakimoto & others, 1963; Takesada, Miyamoto & others, 1965; Creveling & Daly, 1967) or in parkinsonism (Barbeau, de Groot & others, 1963), the issue remains confused, particularly when other reports claim DMPEA to be present in normal controls (Rinne & Sonninen, 1967) and only in small amounts in parkinsonian patients (Boulton & Felton, 1966).Although the original report of Friedhoff & Van Winkle (1962) that DMPEA is present in the pink spot of schizophrenic urine is now largely discredited, the transmethylation theory suggesting aberrant O-methylation still has wide support (Himwich, Narasimhachari & others, 1970). Indeed, both DMPEA and its N-acetyl derivative NADMPEA are known to produce behavioural changes in animals, the latter being the more potent (Bindler, Sanghvi & Gershon, 1968;Friedhoff & Schweitzer, 1968). Although these compounds possess the 4-methoxy group necessary for psychotomimetic activity, neither DMPEA nor NADMPEA produce the hallucigenic effects of the structurally similar mescaline when administered orally to man.In addition, reports claiming that DMPEA is present in parkinsonian urine have been supported by Ernst (1965), Barbeau, Tetreault & others (1966) and Shulgin, Sargent & Naranjo (1969) who showed in animal studies, used as a model for parkinsonism, that DMPEA, 3-hydroxy-4-methoxyphenethylamine (3HMPEA) and mescaline produced the characteristic akinesia in rats.A recent report by Barrass, Coult & Pinder (1972) showed that 3HMPEA but not the isomeric 4HMPEA nor DMPEA itself increased dopamine oxidation and inhibited 5-hydroxytryptamine (5-HT) oxidation in vitro. It was suggested, therefore, that 3HMPEA could be the endogenous toxin in parkinsonism producing akinesia and causing an imbalance in the dopamine: 5-HT ratio. Since DMPEA as well as 3HMPEA produces akinesia in lower animals, the position is clearly complicated. Also, in parkinsonism the substantia nigra, an area of the brain where the biochemical lesion could occur, is reported to be depleted of melanin deposit (Hornykiewicz, 1966) whereas increased dopamine oxidation would lead to increased melanin pigmentation.We wish to draw attention, therefore, to the contentious role of O-methylated derivatives of dopamine in schizophrenia and parkinsonism. The possibility must now be considered that such abnormal metabolites are involved in both diseases. We consider it plausible that 3HMPEA and DMPEA may play a dual role for the following reasons : (1) Both metabolites produce akinesia in animals and may conceivably thus produce the similar syndrome observed in parkinsonism.(2) Both DMPEA and the more potent NADMPEA effect behavioural changes in animals although neither appear to have the hallucigenic activity of mescaline. Although no evidence is yet available it is possibl...

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Relation between the structure of certain methoxyphenylethylaminederivatives and the occurrence of a Hypokinetic Rigid Syndrome

Cited by 54 publications

References 7 publications

On the receptors which mediate the hyperpolarization of salivary gland cells of Nauphoeta cinerea Olivier.

On the receptors which mediate the hyperpolarization of salivary gland cells of Nauphoeta cinerea Olivier.

On the Actions of Compounds Related to Dopamine at a Neurosecretory Synapse

Abnormal O-methylated dopamine metabolites: The endogenous toxins of schizophrenia or parkinsonism?

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