COMT inhibitors: management of Parkinson's disease.
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Antiparkinson Agents↗
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DA agonists -- ergot derivatives: bromocriptine: management of Parkinson's disease.
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Benzophenones↗
Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues.
A random biochemical screening followed by lead optimization culminated in the discovery of Ro 40-7592 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone). Ro 40-7592 was found to inhibit COMT in a competitive fashion both in the CNS and in the periphery (Ki for the liver enzyme = 30 nM). Ro 40-7592 (30 mg/kg p.o.) combined with benserazide (15 mg/kg p.o.) and a low dose of L-DOPA (10 mg/kg p.o.) almost completely blocked (for about 6 h) the formation of 3-O-methyldopa (3-OMD) in brain and plasma, producing a long-lasting increase of L-DOPA in plasma and a parallel marked increase of L-DOPA and dopamine in the brain. Ro 40-7592, combined with peripheral decarboxylase inhibitors and L-DOPA (as in Madopar and Sinemet), will offer substantial advantages in the therapy of Parkinson's disease, i.e. enhanced bioavailability and prolonged plasma half-life of L-DOPA, pronounced DOPA sparing effect and blockade of 3-OMD formation.
Animals↗
Role of monoamine oxidase and catechol-O-methyltransferase in the metabolism of renal dopamine.
Incubation of slices of rat renal cortex with 50 microM L-DOPA during 15 min resulted in the formation of dopamine and of its deaminated (3,4-dihydroxyphenylacetic acid; DOPAC), methylated (3-methoxytyramine; 3-MT) and deaminated plus methylated (homovanillic acid; HVA) metabolites. The presence of pargyline (100 microM) resulted in a 90% reduction in the formation of DOPAC and HVA; levels of dopamine and 3-MT were found to be significantly increased. A concentration dependent decrease in the formation of methylated metabolites was obtained in the presence of (10, 50 and 100 microM) tropolone (10-50% reduction) and (0.1, 0.5, 1.0 and 5.0 microM) Ro 40-7592 (50-95% reduction). Ro 40-7592 was also found to significantly increase DOPAC (20-40%) and dopamine (10-30%) levels, whereas tropolone slightly increased DOPAC (10%) levels. These results show that deamination represents the major pathway in the metabolism of newly formed dopamine under in vitro experimental conditions in the rat kidney. In addition, only when MAO is inhibited does methylation appear to represent an alternative metabolic pathway.
Animals↗
The part played by catechol-O-methyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anaesthetized rabbit.
The present study, carried out in anaesthetized rabbits, aimed at determining the effects of catechol-O-methytransferase (COMT) inhibition on the plasma kinetics of infused 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylalanine (DOPA) as well as on endogenous plasma noradrenaline, DOPEG, DOPA and 3-methoxy-4-hydroxyphenylglycol (MOPEG). The plasma kinetics of infused MOPEG were also evaluated. To block the function of COMT, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) was given intravenously. Dose-finding experiments, in which the drug-induced fall in endogenous plasma MOPEG was used to quantify COMT inhibition, indicated that a Ro 40-7592 dose of 3 mg/kg followed by 1.5 mg/kg every 30 min was sufficient to obtain a virtually complete inhibition of COMT. More than 150 min of COMT inhibition were required for endogenous MOPEG to disappear from plasma, since the plasma half-life of MOPEG was 54 min. COMT inhibition produced marked increases in the plasma levels of endogenous DOPA (1.7-fold) and DOPEG (3.9-fold) and did not alter endogenous plasma noradrenaline. The results concerning the effect of COMT inhibition on the plasma kinetics of infused DOPA and DOPEG were as follows: the plasma clearance of DOPA was not altered, whereas that of DOPEG fell by 41%; the plasma half-life of DOPA increased from 4.9 to 13.0 min and that of DOPEG from 4.8 to 31.0 min; there was an increase in the volume of distribution of DOPA (2 to 3-fold) and DOPEG (4 to 5-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit.
The purpose of this study was to elucidate the finding of Friedgen et al. (1993 b) that catechol-O-methyltransferase (COMT) inhibition is much more effective in increasing the plasma concentration of endogenous dihydroxyphenylglycol (DOPEG) than in increasing the plasma concentration of infused DOPEG. To this end, reserpine-pretreated rabbits were anaesthetized and infused with noradrenaline and/or DOPEG, and the plasma clearances of infused noradrenaline (ClNA) and DOPEG (ClDOPEG) as well as the plasma DOPEG response to noradrenaline infusion [as reflected by the ratio of the steady-state increase in plasma DOPEG (delta DOPEG) to that in plasma noradrenaline (delta NA)] were determined before and after blockade of neuronal uptake by desipramine. Experiments were carried out either under control conditions or after COMT inhibition by i.v. administration of 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592). On the assumption that rates of neuronal noradrenaline uptake equal steady-state rates of neuronal DOPEG formation, the desipramine-sensitive components of ClNA and delta DOPEG/delta NA were used to estimate the apparent plasma clearance of DOPEG formed intraneuronally (Clf-DOPEG) in response to noradrenaline infusion. ClNA was 83.6 ml kg-1 min-1 in the absence and 48.1 ml kg-1 min-1 in the presence of desipramine. Neither the former nor the latter value was altered after COMT inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of CGP 28014 on the in vivo release and metabolism of dopamine in the rat striatum assessed by brain microdialysis.
The effects on rat striatal dopamine (DA) metabolism of systemic and local administration of CGP 28014, an inhibitor of catechol-O-methyl-transferase (COMT), were studied by in vivo microdialysis. CGP 28014 (30 mg/kg i.p.) significantly reduced the levels of homovanillic acid (HVA), but did not modify DA and 3,4-dihydroxyphenylacetic acid (DOPAC). The intrastriatal administration (via the microdialysis probe) of 5, 7.5, 10, and 20 mM of CGP 28014 elicited a concentration-dependent, several-fold increase in extracellular DA but did not alter the levels of HVA and DOPAC. Thus, the effects of CGP 28014 observed after i.p. injection (decrease in HVA levels) are different from those measured after intrastriatal administration (increase in DA release). Therefore, the inhibition of COMT is likely to be due to the action of a metabolite of CGP 28014 formed in the periphery and not in the brain.
3,4-Dihydroxyphenylacetic Acid↗
Central action of benserazide after COMT inhibition demonstrated in vivo by PET.
Positron emission tomography (PET) following intravenous administration of beta-[11C]-L-DOPA provides a method of assessing regional cerebral uptake and utilization of levodopa. Cerebral levodopa kinetics in the rhesus monkey were investigated after the inhibition of catechol-O-methyltransferase (COMT) with RO 40-7592, and after coadministration of the peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors benserazide and carbidopa. Pretreatment with RO 40-7592 (10 mg/kg), benserazide (10 mg/kg) or carbidopa (3.5 mg/kg) did not change striatal k3, which mainly reflects the ability for the brain tissue to convert [11C]-L-DOPA to [11 C]-dopamine, although the brain's uptake of radioactivity increased substantially after pretreatment with the AADC inhibitors. When benserazide was coadministered with RO 40-7592 (10 mg/kg) a dose-dependent decrease in striatal k3 was measured with an apparent ED50 of 3 mg/kg. No such effect was indicated after pretreatment with the combination of RO 40-7592 (10 mg/kg) and carbidopa (3.5 mg/kg). The possible negative interactions of coadministration with COMT inhibitors and predominantly peripherally acting AADC inhibitors must be considered when used in the therapy of Parkinson's disease.
Animals↗
Regional brain kinetics of 6-fluoro-(beta-11C)-L-dopa and (beta-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography.
The regional brain kinetics of (beta-11C)-L-dopa and 6-fluoro-(beta-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 +/- 0.0007 (S.D) and 0.0057 +/- 0.0006 min-1 for (beta-11C)-L-dopa and 6-fluoro-(beta-11C)-L-dopa, respectively. After pretreatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 +/- 0.0015 min-1) for (beta-11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(beta-11C)-L-dopa (0.0092 +/- 0.0015 min-1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(beta-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(beta-11C)-L-dopa significantly contributes to background radioactivity.
Animals↗
Effect of monoamine oxidase A and B and of catechol-O-methyltransferase inhibition on L-DOPA-induced circling behavior.
The effect of enzyme-inhibiting adjuvants on L-DOPA + benserazide-induced contralateral turning in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats was studied. Both the number of turns and the duration of turning were examined. Inhibition of MAO-A with 10 mg/kg Ro 41-1049 increased both parameters; inhibition of COMT with 30 mg/kg Ro 40-7592 had a similar effect. In contrast, inhibition of MAO-B with 10 mg/kg Ro 19-6327 did not change turning behavior. A further potentiation of turning behavior was observed after the combined administration of both the MAO-A and COMT inhibitor. MAO-A inhibition in conjunction with MAO-B inhibition prolonged the duration of L-DOPA-induced turning but had no effect on the number of turns. However, in conjunction with COMT inhibition, 10 mg/kg of the MAO-B inhibitor, Ro 19-6327, significantly affected both the number and duration of turning behavior. An even further potentiation of turning behavior was observed after the combined administration of all three enzyme-inhibitors.
Animals↗
Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS.
In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parkinsonian patients. In the present study the possible effect of DOPS was studied in rats, in which catalepsy was induced with haloperidol as a model for parkinsonian akinesia. Intravenous infusion of NA (1.5 and 15 micrograms/kg) or DOPS (2 and 4 mg/kg) in male Wistar rats (240-290 g) significantly decreased catalepsy. The effect of DOPS was abolished by pretreatment with the peripheral decarboxylase inhibitor benserazide (2 mg/kg). Pretreatment with Ro 40-7592, a catechol-O-methyltransferase inhibitor, potentiated and prolonged the anticataleptic effect of DOPS. The findings suggest a peripheral site of NA mediated anticataleptic action. Therapy with DOPS may be successful only without a peripheral decarboxylase inhibitor. Moreover, the therapeutic effect of DOPS may be potentiated by COMT inhibition.
Animals↗
Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease.
Behavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinson's disease.
Animals↗
Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study.
In vivo microdialysis was used to examine the effect of two new catechol-O-methyltransferase (COMT) inhibitors, Ro 40-7592 and OR-611, on extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in rat striatum. The interactions of the COMT inhibitors with nomifensine, clorgyline and deprenyl were also studied. Ro 40-7592 (3-30 mg/kg, i.p.) decreased dose-dependently the efflux of HVA, increased that of DOPAC, and tended to increase that of dopamine. Higher doses of OR-611 (30-100 mg/kg, i.p.) also decreased the dialysate level of HVA, increased that of DOPAC, and tended to increase that of dopamine. Ro 40-7592 was about ten-fold as potent as OR-611. Neither of the COMT inhibitors changed dialysate levels of 5-HIAA. An OR-611 dose of 10 mg/kg i.p. had no significant effect, in contrast to Ro 40-7592, on any of the parameters studied; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. Both nomifensine (15 mg/kg, i.p.) and clorgyline (4 mg/kg, i.p.) alone elevated extracellular dopamine levels, and lowered those of DOPAC and HVA, though there were quantitative and temporal differences between the drugs. L-Deprenyl (1 mg/kg, i.p.) alone had no significant effect on any of the compounds measured. Ro 40-7592 (10 mg/kg, i.p.) potentiated the effect of nomifensine on dopamine efflux, and it tended to increase clorgyline-induced dopamine efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Determination of the catechol-O-methyltransferase inhibitor Ro 40-7592 in human plasma by high-performance liquid chromatography with coulometric detection.
A sensitive and specific high-performance liquid chromatographic method has been developed to measure the catechol-O-methyl-transferase (COMT) inhibitor 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) in human plasma. The compound and the internal standard were extracted from plasma at pH 2 with n-butyl chloride-ethyl acetate (95:5, v/v). The extract was chromatographed on a reversed-phase column (Hypersil ODS, 5 microns) using a mixture of phosphate buffer (0.05 M, pH 2), methanol and tetrahydrofuran (45:55:5, v/v/v) as the mobile phase. Long-retained components were removed from the system by means of a simple column-switching system. Quantification of the catechol-O-methyltransferase inhibitor was performed by means of coulometric detection (0.1 V). The limit of quantification was about 1 ng/ml, using a 1-ml specimen of plasma. The recovery from human plasma was greater than 88%. The mean inter-assay precision was 5.3% in the range 2.5-1000 ng/ml. Linearity of the standard curve was obtained in the concentration range 2.5-500 ng/ml. The catechol-O-methyltransferase inhibitor was stable in human plasma when stored for six months at -20 degrees C and for 24 h at room temperature. The practicability of the new method was demonstrated by the analysis of more than 400 plasma samples from a tolerance study performed in human volunteers.
Benzophenones↗
Ro 40-7592, a COMT inhibitor, plus levodopa in Parkinson's disease.
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Aged↗
Positron emission tomography in drug evaluation: influence of three different catechol-O-methyltransferase inhibitors on metabolism of [NCA] 6-[18F]fluoro-L-dopa in rhesus monkey.
We compared the influence of three different catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on the metabolism of no-carrier-added (NCA) 6-[18F]fluoro-L-dopa (6-FDOPA) in one Rhesus monkey. All three COMT inhibitors improved 6-FDOPA availability in plasma, increased the specific uptake in the brain and thus improved 6-FDOPA uptake measurements using positron emission tomography (PET). Best results were obtained with Ro 40-7592.
Amidines↗
Synthesis and evaluation of an 18F-labeled dopa prodrug as a PET tracer for studying brain dopamine metabolism.
In the quantitative studies of presynaptic dopamine metabolism by PET with 6-[18F]fluoro-L-dopa (6-[18F]FDOPA), metabolic analysis in the plasma is required to determine the precise input function because of susceptibility of the compound to peripheral metabolism. In this study, we prepared 6-[18F]-fluoro-O-pivaloyl-L-dopa (6-[18F]FPDOPA) as a prodrug of 6-[18F]FDOPA, and evaluated its potential as a PET tracer in mice. If the 6-[18F]FPDOPA is stable peripherally and is hydrolyzed to 6-[18F]FDOPA in the brain tissues, disadvantage of the 6-[18F]FDOPA will be overcome. Compared with the 6-[18F]FDOPA, the initial brain uptake of the 6-[18F]FPDOPA was lower; however, the uptake in the latter become comparable, and the uptake ratios of striatum to other reference regions were larger. Medication of mice with inhibitors of aromatic amino acid decarboxylase and catechol-O-methyl transferase greatly enhanced the striatal uptake of the two compounds. The reduced brain uptake of the compounds by L-phenylalanine-loading suggested transport through the blood-brain barrier by the neutral amino acid transporter. HPLC analysis showed the presence of 6-[18F]FPDOPA, 6-[18F]FDOPA and 6-[18F]fluorodopamine in the striatum; however, 6-[18F]fluoro-3-O-methyl-L-dopa was a predominate metabolite in the brain and plasma as in the case of [18F]FDOPA. Results suggested that 6-[18F]FPDOPA had characteristics as a prodrug of 6-[18F]FDOPA; however, the compound was also labile to metabolic alteration in vivo.
Animals↗
Monoamine oxidase and catechol-O-methyltransferase inhibitors.
Despite advances in the treatment of PD, there remain significant unmet therapeutic needs. This is particularly true at the later stages of the disease when dopaminergic therapy is complicated by motor fluctuations and dyskinesias. Inhibition of dopamine metabolism is a valuable adjunct to exogenous dopaminergic replacement. Inhibitors of MAO-B have been used to treat early and advanced PD for a number of years. Although controversy remains, existing evidence still raises the possibility that MAO-B inhibition may confer a protective effect in PD, delaying the progression of the underlying pathology. More recently, clinically useful inhibitors of COMT have become available. These medications largely act peripherally to increase the pool of available dopamine precursor and prolong the duration of effect of L-dopa. They are indicated primarily for control of motor fluctuations.
Benzophenones↗