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

Abstract

1. The effects of two new synthetic compounds showing in vitro catechol-O-methyl transferase (COMT) inhibitor properties were studied in vivo and compared with the effects of nitecapone and Ro-41-0960. 2. QO IA (3-(3-hydroxy-4-methoxy-5-nitrobenzylidene)-2,4-pentanedione), QO IIR ([2-(3,4-dihydroxy-2-nitrophenyl)vinyl]phenyl ketone), nitecapone and Ro-41-0960 (30 mg kg(-1), i.p.) were given to reserpinized rats 1 h before the administration of L-DOPA/carbidopa (LD/CD, 50:50 mg kg(-1), i.p.). Locomotor activity was assessed 1 h later. All the COMT inhibitors (COMTI), with the exception of QO IA, markedly potentiated LD/CD reversal of reserpine-induced akinesia. Similar results were obtained when the COMTI were coadministered with LD/CD. The effect of compound QO IIR was dose-dependent (7.5-30 mg kg(-1), i.p.). 3. The COMTI (30 mg kg(-1), i.p.) potentiated LD/CD reversal of both catalepsy and hypothermia of reserpinized mice. 4. QO IIR, nitecapone and Ro-41-0960 (30 mg kg(-1), i.p.) reduced striatal 3-methyl-DOPA (3-OMD) levels and increased dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels. Compound QO IA was devoid of any effect on striatal amine levels. In contrast to the other inhibitors, Ro-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 peripherally acting COMT inhibitor in vivo.

Figure 1

Chemical structures of the COMTI.

Figure 2

Effect of COMTI on locomotor activity of reserpinized rats treated with LD/CD. (A) COMTI (30 mg kg⁻¹, i.p.) were administered to rats 1 h before LD/CD (50 : 50 mg kg⁻¹, i.p.) and locomotor activity was measured 1 h later for 1 h. (B) COMTI (30 mg kg⁻¹, i.p.) were coadministered to rats with LD/CD (50 : 50 mg kg⁻¹, i.p.) and locomotor activity was measured 1 h later for 1 h. Reserpinized rats showed akinesia (accumulated counts during 1 h : 36.33±9.49). Results are mean±s.e.mean (n=5–8) of accumulated counts during 1 h. ^**P<0.01 significant difference versus LD/CD treated rats (one-way ANOVA followed by Dunnett's test).

Figure 3

Dose-response curve of the effect of QO IIR coadministered with LD/CD on locomotor activity of reserpinized rats. Increasing doses (7.5–60 mg kg⁻¹, i.p.) of QO IIR were coadministered to rats with LD/CD (50 : 50 mg kg⁻¹, i.p.) and locomotor activity was measured 1 h later for 1 h. Reserpinized rats showed akinesia (accumulated counts during 1 h : 36.33±9.49) Results are mean±s.e.mean (n=5–8) of accumulated counts during 1 h. ^**P<0.01 significant difference versus LD/CD treated rats (one-way ANOVA followed by Dunnett's test).

Figure 4

Effects of COMTI (30 mg kg⁻¹, i.p.) coadministered with LD/CD (50 : 50 mg kg⁻¹, i.p.) on reserpine-induced catalepsy. Results (time spent in the forced posture) are mean (n=5–8); s.e.mean which ranged between 0.00–5.55, were omitted for the sake of clarity. ^**P<0.01 versus reserpinized vehicle-treated animals (repeated measures ANOVA followed by Dunnett's multiple comparison test).

Figure 5

Effects of COMTI (30 mg kg⁻¹, i.p.) coadministered with LD/CD (50 : 50 mg kg⁻¹, i.p.) on reserpine-induced hypothermia. Results (increments in temperature: Δ°C) are mean (n=5–8); s.e.mean, which ranged between 0.12–1.73, were omitted for the sake of clarity. ^**P<0.01 significant difference versus reserpinized vehicle-treated animals (repeated measures ANOVA followed by Dunnett's multiple comparison test).

Figure 6

Striatal amine levels following COMTI and LD/CD administration to reserpinized rats. COMTI (30 mg kg⁻¹, i.p.) were administered 1 h before LD/CD (50 : 50 mg kg⁻¹, i.p.) and rats were sacrificed 2 h later. DA: dopamine; DOPAC: dihydrophenylacetic acid; HVA: homovanillic acid. Results expressed in μg g⁻¹ are mean±s.e.mean (n=5–8). ^*P<0.05 ^**P<0.01 significant difference versus LD/CD treated rats (ANOVA followed by Dunnett's test).

Figure 7

Striatal amine levels following increasing doses of QO IIR (7.5–60 mg kg⁻¹, i.p.) coadministered with LD/CD (50 : 50 mg kg⁻¹, i.p.) to reserpinized rats. Rats were sacrificed 2 h after drug administration. DA: dopamine; DOPAC: dihydroxyphenylacetic acid; HVA: homovanillic acid. Results expressed in μg g⁻¹ are mean±s.e.mean (n=5–8). ^*P<0.05; ^**P<0.01 significant difference versus LD/CD treated rats (ANOVA followed by Dunnett's test).