Identification of major metabolites of the catechol-O-methyltransferase-inhibitor nitecapone in human urine.

Metabolites of nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], a potent new catechol-O-methytransferase-inhibitor, were isolated from human urine both after hydrolysis with beta-glucuronidase and as intact conjugates. Seven phase-I metabolites and corresponding glucuronides were identified using electron ionization and fast atom bombardment mass spectrometry, IR spectroscopy, and proton NMR spectrometry. The most abundant metabolite in urine was the glucuronide of unchanged nitecapone, representing 60-65% of the metabolites found. The main phase-I metabolic reaction was reduction of the side chain double bond and carbonyl groups. One of the major metabolites was formed by cleavage of the side chain by retro aldol condensation. All phase-I metabolites were present mainly as their glucuronic acid conjugates. The 3-nitrocatechol-structure of nitecapone seems to hinder nitro-reduction, catechol-O-methylation, and sulfation reactions.

Synthesis of some novel potent and selective catechol O-methyltransferase inhibitors.

A series of disubstituted catechol derivatives was synthesized and tested as potential COMT inhibitors. The most active compounds were more than 1000 times more potent (IC50 = 3-6 nM) in vitro than the known COMT inhibitor, 3',4'-dihydroxy-2-methylpropiophenone (U 0521, IC50 = 6000 nM). The new compounds were also highly selective COMT inhibitors with no activity against other essential enzymes involved in the synthesis and metabolism of catecholamines.

Inhibition of cardiac phosphodiesterase III by the novel cardiotonic agent 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride.

The novel cardiotonic agent 6[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154) was investigated for its cardiovascular effects and its mechanism of action. In the anaesthetized rat MCI-154 (0.01-0.3 mumol/kg i.v., bolus injection) produced a dose-dependent increase in left ventricular dP/dt, and a decrease in mean arterial pressure. A relatively small increase in heart rate was observed. The drug inhibited selectively canine cardiac phosphodiesterase III (IC50 2.5 +/- 0.6 mumol/l). In skinned porcine trabeculae, MCI-154 produced only a small increase in the Ca2+-sensitivity of the contractile proteins. The results suggest that MCI-154 is a potent cardiotonic agent, and that inhibition of phosphodiesterase III may be a important component of this effect.

Synthesis and antihypertensive activity of some new quinazoline derivatives.

A series of substituted 2-piperidino-4-amino-6,7-dimethoxyquinazolines was synthesized and screened as potential antihypertensive agents. The hypotensive effect of all the new compounds was studied after intravenous administrations in urethane-anesthetized normotensive rats. The furoylpiperazine moiety in the prazosin molecule could be replaced by a more stable substituted piperidine group without loss of the blood pressure lowering activity. However, the nature of the substituent profoundly influenced the hypotensive potency as well as the duration of the hypotensive action. Some of the new compounds were found to be as potent as prazosin. On the basis of potency and the duration of the hypotensive action in the anesthetized rats, five of the most promising compounds were selected for further studies. Each of these agents exerted an antihypertensive effect upon oral administrations in conscious spontaneously hypertensive rats. At small doses, the new compounds appeared to be somewhat less potent than prazosin, but at the higher doses of 10-100 mumol/kg, two of them appeared to be even more efficacious antihypertensive agents than prazosin.

The effect of iron, tin, aluminium, and chromium on fading, discoloration, and precipitation in berry and red beet juices.

The effect of iron(II), tin(II), aluminium(III), and chromium(III) on the properties of red whortleberry, blackcurrant, and red beet juices was followed during storage for 10 months at 5 degrees C. The colour and pH changes were studied, and the precipitates formed were weighed and their metal contents assayed. Of the metals tested, only tin caused bluish discoloration in the berry juices. In the case of iron, aluminium, and chromium the low pH prevented this type of discoloration. In berry juices, some increases in colour intensity took place with the lowering of pH value, whereas in red beet juice the opposite change occurred. The colour changes due to storage appear to take place irrespective of the metals. Precipitation is enhanced in red whortleberry juice only by tin, and in blackcurrant juice by tin and iron. In red beet juice, precipitation is increased by the lowering of pH resulting from metal salt addition. In general, increase in the amount of metal added increased the metal content of the precipitate. Iron showed the greatest tendency to become bound in the precipitate, particularly in blackcurrant and red beet juice. The suitabilities of the metals for canning purposes are considered. Chromium, in particular, has interesting possibilities in view of the low degree of colour change associated with it.