A Study of the Behavioural and Neurochemical Effects of Deuterium Substitution in DL-DOPA, Dopamine and B-Phenylethyhydrazine
Date
1986
Authors
Journal Title
Journal ISSN
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Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
Deuterium, the stable heavy isotope of hydrogen, has twice the
relative mass of hydrogen; as a consequence, the vibrational frequency
of a carbon-deuterium bond is lower than that for the corresponding
bond to hydrogen. The energy requirement for cleavage of a carbondeuterium
bond is greater than that for a carbon-hydrogen bond; therefore,
chemical bonds involving deuterium will generally be more stable
than those involving hydrogen. Where cleavage of a bond is rate-determining,
substitution of deuterium for hydrogen in this position will
result in an isotope effect. Thus, it may be possible to enhance the
half-life of a drug, and hence its duration of action, through deuterium
substitution. Monoamine oxidase catalyses the oxidative dealnination
of various amines by removal of the amine group, in a reaction that
involves the formation of an imine intermediate. The production of the
imine, which involves the removal of a hydrogen from the a-side chain
carbon atom, is rate limiting for this reaction and, consequently,
deuterium labelling on the a-carbon atom may be expected to attenuate
the rate of oxidative metabolism by monoamine oxidase. The monoamine
oxidase inhibitor phenelzine is inactivated by monoamine oxidase in a
reaction that is analogous to that of amine oxidation. This research
was directed towards examining the effects of deuterium substitution in
DL-dopa, dopamine, and phenelzine and to investigate whether deuterium
labelling of the a-positions of these drugs attenuates their metabolism
by monoamine oxidase and hence enhance their behavioural and neurochemical
activity. Since DL-dopa and phenelzine are clinically effective
-idrugs
used in the treatment of Parkinson's disease/syndrome and atypical
depression, respectively,substitution of deuterium for hydrogen on
the a-positions of these drugs may effectively increase their clinical
efficacy.
Our results are consistent with earlier observations that DL-dopa
induces a stereotyped behavioural syndrome in rats with a concomitant
increase in striatal dopamine levels and no change in hypothalamic
noradrenaline concentrations. Deuterium substitution in the a,B,Bpositons
of DL-dopa did not influence the ability of this drug to
elicit behavioural activation or to alter central catecholamine levels
.:!.!!. vi vo, sugges ti ng that deuteri urn-l abe 11 i ng does not protect the
subsequently formed [2U3]-dopamine from metabolism by monoamine oxidase
or dopamine-8-hydroxylase. Despite the observation that dopamine
induces a dose-dependent contraversive circling, with a simultaneous
elevation in striatal dopamine concentration, in rats with unilateral
6-0HDA lesion of the nigrostriatal pathway, deuterium sUbstitution does
not influence the behavioural or neurochemical activity of this drug.
In contrast, the replacement of deuterium on the a,a,8,8-positions of
phenelzine profoundly increases the behavioural activation of this drug
at a time period 2-12 hours after drug administration. This increased
behavioural excitation, 6 hours after drug treatment, seems to be more
closely associated with elevations in central phenylethylamine and
tryptamine levels than to increases in brain dopamine, noradrenaline,
or serotonin concentrations. The ability of deuterium substitution to
-i ienhance
the activity of phenelzine appears to be related to an attenuation
of the metabolic inactivation of [2H]4-phenelzine by monoamine
oxidase. Deuterium substitution in the a-positions of phenelzine may,
therefore, provide a means by which the clinical efficacy of this drug
can be enhanced.
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Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Psychiatry
Program
Department of Psychatry, Ph.D