Different modes of action of catecholamine-O-methyltransferase inhibitors entacapone and tolcapone on adenylyl cyclase activity in vitro.

Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone are used as adjuncts to L-DOPA ( l-3,4-dihydroxyphenylalanine, levodopa) in the treatment of Parkinson's disease. Tolcapone has been reported to associate with diarrhoea, a common reason for study withdrawal. The mechanism of this adverse effect is not yet understood. Cholera toxin causes diarrhoea by permanent activation of G(s) proteins, resulting in increased adenylyl cyclase (AC) activity. The aim of this study was to examine the effects of the COMT inhibitors entacapone and tolcapone on AC activity in membranes isolated from rat striatum, a brain structure enriched with dopaminergic G-protein-coupled receptors and AC activity. This study demonstrates differential effects of tolcapone and entacapone on Gpp(NH)p/dopamine-stimulated AC activity. Entacapone enhanced the stimulatory effect of Gpp(NH)p/dopamine, whereas tolcapone attentuated this effect, suggesting that diarrhoea associated with tolcapone treatment is not caused by permanent activation of G(s) proteins.