File:Catechol-O-methyltrasferase in complex with SAM (ball-and-stick model) and Opicapone (pink).png

English: Feel free to use this image, just link to www.enzymlogic.com. Work done with the molecular visualization VMD program developed at the University of Illinois: www.ks.uiuc.edu/Research/vmd/

Catechol-O-methyltransferase (COMT) is involved in the inactivation of the catecholamines such as dopamine, epinephrine or norepinephrine. The enzyme introduces a methyl group to the catecholamine, which is donated by S-adenosyl methionine (SAM). Levodopa, a precursor of catecholamines, is the most effective symptomatic treatment of Parkinson’s disease. However, following oral administration, levodopa is rapidly metabolized in the periphery by aromatic L-aminoacid decarboxylase (AADC) and catechol- O-methyltransferase (COMT). COMT inhibitors, like entacapone, save levodopa from COMT and prolong the action of levodopa. Entacapone is considered to be safe, but its efficacy is limited and requires frequent dosing. Therefore, there is an unmet need for the development of new COMT inhibitors with a better therapeutic profile and more convenient dosage regimen, namely once-daily administration.

Recent studies show that opicapone is a long-acting COMT inhibitor. COMT inhibition in human erythrocytes (t1/2 = 62 h, koff = 3.1x10-6 s-1) compares well to the estimated dissociation rate constant of the COMT–opicapone molecular complex (koff = 1.9x10-6 s-1). Despite the low plasma exposure and short clearance t ½ of opicapone, the levels of erythrocyte COMT inhibition are sustained far beyond the point of plasma drug clearance (8–12 h).

Researchers propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone and provide a basis for further clinical development of opicapone in once-daily dosage regimen.