Possible New Metabolites mediating Actions of L-Dopa

Abstract

IT is generally assumed that the pharmacological actions of L-dopa (L-3,4-dihydroxyphenylalanine) are mediated through its conversion to dopamine. Thus, the specific value of L-dopa in the treatment of Parkinson's disease^1–4 would lie in its ability to traverse the blood–brain barrier and undergo de-carboxylation in the parenchymal cells of the brain. It is likely that this mechanism operates physiologically in certain systems. But is dopamine the only metabolite mediating the action of L-dopa^4–7? Some other simple derivative, formed in the brain by “conventional” pathways, may be pharmacologically active and responsible for the stimulation of dopamine-sensitive receptors that have been deprived of their normal presynaptic connexions through degenerative processes, as in Parkinson's disease, or by stereotaxically placed lesions in experimental animals^8–10. Another possibility lies in the conversion of L-dopa or one of its immediate products to some quite different compound, for example by condensation of dopamine with an aldehyde to form a tetrahydroisoquinoline. Reactions of this type are known for pyridoxal and its phosphate^11–13, as well as for 3,4-dihydroxyphenylacetaldehyde. The last compound arises from dopamine through the action of monoamine oxidase, and can condense non-enzymatically with dopamine to form tetrahydropapaveroline (nor-laudano-soline)¹⁴ as shown in Fig. 1. A Scruff's base is an intermediary in the reaction. Tetrahydropapaveroline possesses hypotensive activity¹⁴. It is conceivable that a benzyltetrahydroisoquinoline, derived from L-dopa in vivo, has at least some of the pharmacological activities ascribed to this amino-acid in Parkinson's disease⁷. The type reaction described here has been demonstrated in vivo;, in this case, 1-methyl-l,2,3,4-tetrahydroisoquinolines are formed^15,16 by the condensation of catecholamines with acetaldehyde, the immediate dehydrogenation product of ethanol.