A Study of the Behavioural and Neurochemical Effects of Deuterium Substitution in DL-DOPA, Dopamine and B-Phenylethyhydrazine

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.