In vivo effects of new inhibitors of catechol-O-methyl transferase

1 The effects of two new synthetic compounds showing in vitro catechol-O-me thyl transferase (COMT) inhibitor properties were studied in vivo and compa red with the effects of nitecapone and Ro-41-0960. 2 QO IA (3-(3-hydroxy-4-methoxy-5-nitrobenzylidene)-2,4-pentanedione), QO I IR ([2-(3,4-dihydroxy-2-nitrophenyl)vinyl]phenyl ketone), nitecapone and Re -41-0960 (30 mg kg(-1), i.p.) were given to reserpinized rats 1 h before th e administration of L-DOPA/carbidopa (LD/CD, 50:50 mg kg(-1), i.p.). Locomo tor activity was assessed Ih later. All the COMT inhibitors (COMTI), with t he exception of QO IA, markedly potentiated LD/CD reversal of reserpine-ind uced akinesia. Similar results were obtained when the COMTI were coadminist ered with LD/CD. The effect of compound QO IIR was dose-dependent (7.5-30 m g kg(-1), i.p.). 3 The COMTI (30 mg kg(-1), i.p.) potentiated LD/CD reversal of both catalep sy and hypothermia of reserpinized mice. 4 QO IIR, nitecapone and Re-41-0960 (30 mg kg(-1), i.p.) reduced striatal 3 -methyl-DOPA (3-OMD) levels and increased dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) levels. Compound QO IA was devoid of any effect on stri atal amine levels. In contrast to the other inhibitors, Re-41-0961 reduced HVA levels as well. The effect of QO IIR on striatal amine levels was dose- dependent (7.5-60 mg kg(-1), i.p.) 5 These results suggest that the new compound QO IIR is an effective periph erally acting COMT inhibitor in vivo.