Tolcapone

Tolcapone (brand name Tasmar) is a selective, potent and reversible nitro catechol type inhibitor of enzyme catechol-O-methyl transferase (COMT).

Uses

Tolcapone is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication that is conventionally paired with an aromatic L-amino acid decarboxylase (AADC) inhibitor.

Tolcapone has come to show promise in the treatment of Hallucinogen Persisting Perception Disorder, which is theorized to be an anomaly in executive function brought on by COMT dis-inhibition in the brain, by which Tolcapone has shown to reduce symptoms by inhibiting COMT breakdown, decreasing visual symptoms.

Normally, administration of levodopa is compromised when COMT converts it to 3-methoxy-dopa. By preventing this effect, more of the levodopa that is administered reaches the CNS. Additionally, levodopa that is in the CNS, after being converted to dopamine, will not be degraded by COMT when tolcapone inhibits COMT activity.

Chemistry

Tolcapone is a yellow, odorless, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25. The chemical name of tolcapone is 3,4-dihydroxy-4’-methyl-5-nitrobenzophenone. Its empirical formula is C₁₄H₁₁NO₅.

History

Tolcapone was introduced into European Market August 1997 and subsequently into the United States Market in March 1998. Liver toxicity or hepatoxicity was reported in four people who were administered Tolcapone, 3 people died due to complications. Consequentially, the marketing authorization of Tolcapone was suspended from December, 1998 to August, 2004 when it was lifted. In November 1998, the company that manufactured Tasmar© voluntarily removed the drug from the market. The authorization was then renewed on August, 2009.

As a result of reported complications, the U.S. Food and Drug Administration (FDA) issued a black-box warning for Tasmar and label revisions that aimed to regulate the monitoring of those prescribed Tasmar or Tolcapone for PD in November 1998.

Unlike the United States, at the time a number of other countries withdrew Tasmar or Tolcapone from the market; Australia in February 1999, Bulgaria in April 1999, Iceland in November 1998, Lithuania in December 1998.

Synthesis

Although not the first reported synthesis, the following is a fast, effective and environmentally conscious way to synthesize Tolcapone.

1. The synthesis starts with the product 4-benzyloxy-3-methoxybenzaldehyde which is reacted with p-tolylmagnesium bromide to yield 1-(4-Benzyloxy-3-methoxyphenyl)-1-(4-methylphenyl)methanol.
2. This is then reacted with sodium tert-butoxide in toluene to yield ( 1-(4-Benzyloxy-3-methoxyphenyl)-1-(4-methylphenyl)methanone.
3. This is then reacted with ammonium formate to yield 1-(4-Hydroxy-3-methoxyphenyl)-1-(4-methylphenyl)methanone.
4. This is then mixed with nitric acid to yield 1-(4-Hydroxy-3-methoxy-5-nitrophenyl)-1-(4-methylphenyl) methanone.
5. Aluminum chloride was added to the preceding product to yield 1-(3,4-Dihydroxy-5-nitrophenyl)-1-(4-methylphenyl)methanone (Tolcapone).

Pharmacodynamics

Tolcapone binds to the catalytic center of COMT in both peripheral and central nervous systems with greater affinity than any of the three catecholamine, including Levodopa (L-DOPA). It thereby prevents the 3-0-methylation of L-DOPA (3-hydroxy-L-tyrosine) by COMT which produces 3-0-methyldopa (3-methyoxy-l-tyrosine), a major metabolite that competes with L-DOPA to cross the blood-brain barrier. Thus Tolcapone improves the bioavailability and reduces the clearance of L-DOPA and subsequently dopamine from the central nervous system (CNS).

The strength of the binding affinity of Tolcapone, represented by the inhibition constant Ki (2.50 nM), can be thought of as the dissociation constant for enzyme and inhibitor complex kinetics. Maximum catalytic activity denotes the efficacy of Tolcapone (Vmax=58.4 pmol/min*mg).

Pharmacokinetics

Typical dose of Tolcapone is 100 or 200 mg, orally administered three times daily. The half life of Tolcapone is 2â€"3 hours, volume of distribution (Vd) being 0.3L/kg (21 L in average 70 kg person) and bioavailability about 60%.

Tolcapone has the ability to cross the bloodâ€"brain barrier and thus exerts its COMT inhibitory effects in the central nervous system (CNS) as well as in the periphery.

99% of Tolcapone is in monoanionic form when in body because the physiological pH is 7.4. Tolcapone penetrates the blood-brain barrier better than two other nitrocatechols (nitecapone, entacapone) because it has higher Lipophilicity due to its R substituent. Partition coefficients quantify the ability of the molecule to cross the blood-brain barrier. LogPIdce= 0.2, -1.4, -0.4 for Tolcapone, nitecapone and entacopone respectively.Partition coefficients in this case were measured in 1,2-dichloroethane / H₂O solution which caused molecules to be in ionized form. There is no current explanation for how these charged molecules permeate the blood-brain barrier.

Treatment

Tolcapone is administered adjunct with Levodopa and AADC because it increases the bioavailability of L-DOPA. Since Tolcapone has a greater affinity for COMT, it inhibits the enzyme from methylating levodopa. This results in greater levels of L-DOPA and increases the time period before clearance.

Tolcapone helps alleviates the issues with L-DOPA 50% of PD patients have experienced. Without administration of Tolcapone, the beneficial effects of L-DOPA have worn off resulting in motor fluctuations.

In comparison with entacapone, another nitro catechol COMT inhibitor, Tolcapone has longer half life (2.9 hours vs. 0.8 hours), and can better penetrate the blood-brain barrier in that it acts both centrally and peripherally. However, entacapone is less toxic in regard to liver function.

Adverse effects

Tolcapone has demonstrated significant hepatotoxicity that limits the drug's utility. Entacapone, another COMT inhibitor, is an alternative selection for L-DOPA adjunct therapy in the treatment of Parkinson's disease, largely since it has a more favorable toxicity profile.

This hepatoxicity can be attributed to elevated levels of transminases, but studies have shown that minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored. No clear mechanism is implicated in tolcapone induced liver toxicity, but it has been hypothesized that it has something to do with abnormal mitochondrial respiration due to the uncoupling of oxidative phosphorylation.

Other side effects that result from the administration of tolcapone regard the increase in dopaminergic activity, digestive symptoms and liver function. Treatment with tolcapone runs the risk of eliciting or prolonging dyskinesia; this can be counteracted by decreasing the dose of L-DOPA. This occurs because the administration of tolcapone results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that works to induce symptoms of PD.

Digestive symptoms include nausea, diarrhea, orthostatic hypotension, urine discoloration and dizziness. Tolcapone causes more severe diarrhea than entacapone.

See also

• Entacapone
• Drug of last resort

References

External links

• Tolcapone bound to proteins in the PDB