Catechol-O-methyltransferase (COMT): Biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors

Abstract

COMT O-methylates catecholamines and other compounds with a catechol structure. The general function of COMT is the elimination of biologically active or toxic catechols and some other hydroxylated metabolites. During the first trimester of pregnancy, COMT present in the placenta protects the developing embryo from activated hydroxylated compounds. COMT also acts as an enzymatic detoxicating barrier between the blood and other tissues shielding against the detrimental effects of xenobiotics. COMT may serve some unique or indirect functions in the kidney and intestine tract by modulating the dopaminergic tone; the same may be true in the brain: COMT activity may regulate the amounts of active dopamine and norepinephrine in various part of the brain and therefore be associated with the mood and other mental processes. There is one single gene for COMT, which codes for both S-COMT and MB-COMT using two separate promoters. Both rat and human S-COMTs contain 221 amino acids, and their molecular weights are 24.8 and 24.4 kD, respectively. Rat MB-COMT contains 43 and human MB-COMT contains 50 additional amino acids, of which 17 (rat) and 20 (human) are hydrophobic membrane anchors. The remainder of the MB-COMT molecule is suspended on the cytoplasmic side of the intracellular membranes. Rat S-COMT has been recently crystallized at 1.7- to 20-Å resolution. The active site of COMT consists of the AdoMet-binding domain and the actual catalytic site. The catalytic site is formed by a few amino acids that are important for the binding of the substrate, water, and Mg2+ and for the catalysis of O-methylation. The Mg2+, which is bound to COMT only after AdoMet binding, improves the ionization of the hydroxyl groups. The lysine residue (Lys144), which accepts the proton of one of the hydroxyls, acts as a general catalytic base in the nucleophilic methyl transfer reaction. A series of new and highly selective COMT inhibitors have been developed. Entacapone, nitecapone, and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (K(i) in nanomolar range), whereas CGP 28014 is a hydroxypyridine derivative and ineffective in vitro. In animal studies, these compounds effectively inhibit the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioral effects. Entacapone and nitecapone have mainly a peripheral effect, whereas tolcapone and CGP 28014 also inhibit the O-methylation in the brain. In human volunteers, entacapone, nitecapone, and tolcapone dose- dependently inhibit the COMT activity of erythrocytes, improve the bioavailability of L-dopa, and inhibit the formation of 3-OMD. In clinical studies in PD patients, both entacapone and tolcapone potentiate the therapeutic effect of L-dopa and prolong the daily on time by 1 to 2 h. The two marketed COMT inhibitors have different treatment strategies, advantages, and disadvantages, which are listed in Table 11. In the clinic, COMT inhibitors have been well tolerated, and the number of premature terminations has been low. In general, the incidence of adverse events has been higher in tolcapone-treated patients than in entacapone-treated patients. The main events have consisted of dopaminergic and gastrointestinal problems. Dopaminergic overactivity causes an initial worsening of levodopa-induced dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders, and hallucinations. Tolcapone has been associated with diarrhea in about 16 to 18% of cases, and entacapone has been associated in less than 10% of cases. Diarrhea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the color of COMT inhibitors and their metabolites. Elevated liver transaminate levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. Three cases of acute, fatal fulminant hepatitis have been described in association of tolcapone when more than 100,000 patients have been treated. In addition, a few potentially fatal neurological adverse reactions, including neuroleptic-like malignant syndrome, have described. Because of these serious adverse drug reactions, tolcapone marketing was suspended in Europe and Canada. In early 1999, no restrictions of the use of entacapone have been proposed.