Introductory Remarks

Catechol-O-Methyltransferase Inhibition—An Innovative Approach To Enhance L-Dopa Therapy In Parkinson's Disease With Dual Enzyme Inhibition

Erkki Nissinen    Orion Corporation, Orion Pharma, Research and Development, Research Center, Espoo, Finland

Abstract

Catechol-O-methyltransferase (COMT) enzyme and its inhibition have been closely related to the treatment of Parkinson’s disease (PD) patients with motor fluctuations needing enhancement of their levodopa (L-dopa) therapy (L-dopa/dopa decarboxylase inhibitor), this indication being so far the only clinical application of COMT inhibitors. L-dopa treatment has remained the most effective therapy for PD, but its further development has been quite a challenge mainly due to the effective metabolism of L-dopa in the human body by multiple pathways, decarboxylation and O-methylation being the two most important of them. The introduction of clinically effective and safe COMT inhibitors has greatly increased the usefulness of L-dopa therapy, but how to utilize the full potential of L-dopa is still unsolved leaving a need for more potent COMT inhibitors.

Keywords

COMT

COMT inhibition

dopa decarboxylase

L-dopa

dopamine

Parkinson’s disease

I Introductory Remarks: Catechol-O-Methyltransferase Inhibition: An Innovative Approach to Enhance L-dopa Therapy in Parkinson's Disease with Dual Enzyme Inhibition

The biochemical finding by Arvid Carlsson some 50 years ago that dopamine was a neurotransmitter and that levodopa (L-dopa) could act as its precursor capable of penetrating into the brain (Carlsson et al., 1957) was surprisingly rejected by the scientific community at a CIBA Foundation meeting in London (Carlsson 2002). But as usual some scientists were leading the way forward with this new idea to become pioneers to discover and report an autopsy finding that nucleus caudatus and putamen (striatum) contained higher dopamine concentrations compared with other investigated brain regions, and that those levels were markedly reduced in two adult patients with idiopathic Parkinson’s disease (PD) (Ehringer and Hornykiewicz, 1960). This epoch-making finding eventually led to attempts to increase the decreased amounts of dopamine in the brain first by intravenous administration of the natural dopamine precursor L-dopa to treat the PD patients (Birkmeyer and Hornykiewicz, 1961), followed by oral administration. L-dopa was subsequently introduced into clinical practice during 1967–1969 when Cotzias published papers (Cotzias, 1968; Cotzias et al., 1969), establishing the principles of the L-dopa therapy as we now know it today. The US Food and Drug Administration approved L-dopa as a drug to be used in the treatment of PD in 1970. Finally, Lloyd et al. (1975) showed using postmortem brain tissues of PD patients that L-dopa treatment increased the dopamine concentration 10–15 times compared to untreated controls. However, L-dopa is a very tricky molecule; when given alone, it is metabolized quickly most likely in the gut and liver mainly (70%) by aromatic L-amino acid decarboxylase (AADC), also called dopa decaboxylase (DDC), leading to formation of dopamine already in the periphery.

Scientists figured out quite soon after the discovery of L-dopa therapy that adding of a peripherally acting AADC inhibitor benserazide or carbidopa to the treatment, L-dopa dose could be reduced to one tenth of the original levels and at the same time more L-dopa could be delivered into the brain (Pletscher and Bartholini, 1971). In the brain, L-dopa is taken up by the surviving neurons and converted to dopamine. Dopamine is stored in the available neuronal vesicles and released into synaptic space to be taken up by the postsynaptic dopaminergic receptors. However, when the decarboxylation pathway is being inhibited, the Nature which is clever in protecting us has decided that O-methylation route takes over (Nutt and Fellman, 1984) leading to the formation of large quantities of the long-lived inert L-dopa metabolite 3-O-methyldopa (3-OMD), which can compete with L-dopa to be taken up through the neutral amino acid transporters in the gut and blood–brain barrier.

The first attempts to develop clinically useful (safe and efficacious) catechol-O-methyltransferase (COMT) inhibitors, the first-generation COMT inhibitors, were disappointing. The catechol-structured compounds which showed reasonable potency in vitro had rather modest selectivity for COMT. Furthermore, they had both safety problems and poor efficacy in experimental models. New development was started at 1980s and the discovery of nitrocatechols led to clinical use of two new COMT inhibitors: entacapone (Comtess®/Comtan®) and tolcapone (Tasmar®). These compounds are highly selective COMT inhibitors and an order of magnitude more effective in biochemical terms than the first-generation catechol-structured COMT inhibitors (Borgulya et al., 1989; Männistö et al., 1988). Of these two compounds, mainly peripherally acting entacapone has proven to be well tolerated in clinical use while tolcapone, which also has central activity, seems to be associated with liver function abnormalities, restricting its clinical use with the need to check the liver function before starting the treatment and continuing monitoring hepatic laboratory parameters thereafter. Anyway, both compounds when given together with DDC inhibitors (DDCI) reduce L-dopa metabolism to 3-OMD increasing L-dopa bioavailability significantly. This means that administration of COMT inhibitor with L-dopa/carbidopa or L-dopa/benserazide therapy allows more stable plasma levels of L-dopa (Nutt et al., 1994) leading to more continuous L-dopa availability in the brain (Müller et al., 2006) compared to administration of L-dopa/DDCI alone, as shown in the graphic presentation in Fig. 1.

L-dopa therapy has a clear beneficial effect on the course of PD and no other more efficacious treatment has yet been developed (Schapira et al., 2009). Unfortunately, chronic use of L-dopa leads to development of some undesirable complications in most patients. Nevertheless, L-dopa is the gold standard in the treatment of PD—the closer the drug is to the corresponding natural neurotransmitter, the better the efficacy is likely to be. And—L-dopa is close—taken up into the brain, where it is converted to dopamine with efficacy unreachable by any other compound trying to mimic the action of the one available naturally in the brain. Additionally, it is good to keep in mind that L-dopa transferred to dopamine in the brain can stimulate D1- and D2-receptors, but it can also activate adrenoceptors since it is further metabolized to noradrenaline, which has been shown to have reduced brain levels in PD (Riederer et al., 1977). The features distinguishing L-dopa from dopamine agonist therapy have been excellently reviewed by Mercuri and Bernardi (2005).

In PD the buffering capacity for L-dopa in the brain is diminished since dopaminergic nerve terminals are gradually lost during the disease progression. The beneficial effect of more stable blood levels of L-dopa is seen especially during L-dopa infusion therapy (Stocchi et al., 2005), which is as one can imagine quite challenging. Another solution for continuous dopaminergic stimulation is the so-called Duodopa system, where a microsuspension gel of L-dopa and carbidopa is pumped directly into the duodenum via a surgically implanted cannula. Again, this treatment is invasive and expensive although the results have been good (Nyholm, 2006). Much more convenient would be the delivery of L-dopa via skin patch, which is challenging due to its physicochemical properties, poor solubility, and permeation—properties which require a large patch but hopefully new technologies could help to solve this problem. The stabilization of the plasma levels of L-dopa after oral administration using sustained release formulations or prodrugs of L-dopa has been an ongoing effort for a long time, though the final clinical success is still awaited. Advances made in L-dopa therapy until the date include developing a combined formulation containing the dual enzyme inhibition of DDC and COMT by carbidopa and entacapone in one tablet, which has both been preferred by PD patients experiencing wearing-off, by reducing the number of daily pills needed (Myllylä et al., 2006), as well as shown significant improvement in efficacy, when switched to from...