Metabolism of BW 1370U87 in rat,dog, and man

BW 1370U87 is a potent, selective inhibitor of rat and human brain MAO-A. The plasma concentrations of BW 1370U87 and its metabolites were determined in rat, dog, and man. After an oral dose, BW 1370U87 undergoes extensive first-pass metabolism in all species studied. The 1-(1,2, dihydroxyethyl) metabolite, BW 1003U88, was a major metabolite in rat, dog, and human plasma. The 1-(1-hydroxyethyl) metabolite, BW 183U88, was a major metabolite in dog plasma, whereas it was present in much lower concentrations in the rat and man. Both BW 1003U88 and BW 183U88 are active MAO-A inhibitors although not as active as the parent compound. The inactive 1-(2-acetic acid) metabolite, BW 1552U88, was a major metabolite in rat plasma but a minor metabolite in the dog. Plasma concentration versus time profiles in both rat and man suggest that the metabolites undergo enterohepatic recycling. Although plasma concentrations of BW 1370U87 were relatively low compared to the metabolites, the concentrations detected in rat and man after a 50 mg/kg or 400 mg oral dose, respectively, exceeded the IC₅₀ value measured in rat and human brain. Furthermore, the time course of MAO-A inhibition appears to follow the plasma concentration versus time profile of BW 1370U87 in the rat. Preliminary experiments in rats indicate that BW 1370U87 and its metabolites distribute into brain and inhibit MAO-A.     

Mechanism of monoamine oxidase-A inhibition by BW 1370U87

BW 1370U87 is a potent, selective inhibitor of rat and human MAO-A with a competitive mechanism of action. K_i = 0.01 μM with either serotonin or tyramine as substrate. After preincubation of BW 1370U87 with mitochondrial MAO, full enzyme activity was restored by dialysis. Following oral administration to rats, BW 1370U87 inhibited brain MAO-A in a dose-dependent manner, with a duration greater than 6 hr, but less than 24 hr. No significant inhibition of MAO-B by BW 1370U87 was observed either in vitro or ex vivo. The selectivity, reversibility, and competitive kinetics of the inhibition by BW 1370U87 may contribute to an improved safety profile with this novel MAO-A inhibitor.     

Blood pressure effects of monoamine oxidase inhibitors in response to orally administered tyramine in the rat

The reversible monoamine oxidase-A inhibitors BW 1370U87, BW 616U76, brofaromine, and moclobemide, and the irreversible nonselective monoamine oxidase inhibitor phenelzine were compared for potentiation of the pressor response to oral tyramine. Conscious rats were pretreated with doses of the monoamine oxidase inhibitors sufficient to produce 80% inhibition of brain monoamine oxidase, and then were challenged with orally administered tyramine. Blood pressure was monitored prior to and after tyramine, and peak pressor responses were compared. At a dose of 15 mg/kg tyramine, the pressor response of BW 1370U87 was statistically similar to the vehicle control response. BW 616U76, brofaromine, and moclobemide elicited mild tyramine pressor effects, whereas phenelzine resulted in a marked elevation of blood pressure. Higher doses of tyramine elicited blood pressure elevations from all of the monoamine oxidase inhibitors.     

BW 1370U87, a new monoamine oxidase-A inhibitor: Effects on biogenic amine neurotransmitter and metabolite levels in rat brain

Monoamine oxidase (MAO) inhibitors increase brain concentrations of biogenic amines and decrease concentrations of the acidic metabolites of biogenic amines. It has been suggested that the magnitude of these effects is an indicator of MAO inhibition. Oral doses of BW 1370U87, moclobemide, and brofaromine were given to rats at doses previously shown to induce brain MAO-A inhibition by at least 80%. The effects on brain biogenic amines and their metabolites were quantified 2 and 4 hr after oral dosing using HPLC with electrochemical detection. Moclobemide and BW 1370U87 induced larger increases in 5HT, NE, and DA and larger decreases in DOPAC, 5HIAA, and HVA than did brofaromine at the doses tested. At 8 hr post-dose the effects of BW 1370U87 on 5HT, NE, DOPAC, and HVA were still significant (P≤0.05), and the time course was similar to that seen following moclobemide and brofaromine treatment. Only BW 1370U87 increased brain concentrations of biogenic amines at a dose that does not significantly potentiate pressor effects of orally administered tyramine.     

Effect of a novel monamine oxidase-a inhibitor,bw 1370U87, on urinary 3-methoxy-4-hydroxyphenylglycol in normal volunteers

Urinary 3-methoxy-4-hydroxyphenlglycol (MHPG) levels were measured in 14 normal volunteers during a Phase I study of the novel, reversible monoamine oxidase-A (MAO-A) inhibitor BW 1370U87 targeted for the treatment of depression. baseline MHPG excretion (day 0) showed a significant diurnal increase (n = 14, P < 0.05) between 1200 and 2000 h. Oral administration of BW 1370U87 produced significant (35-45% maximal, P < 0.05) decreases from these basal levels during the same 1200-2000 h time interval Twenty-four hours after the dose (dose was given at 0800 h), urinary MHPG levels returned to baseline, consistent with a reversible mechanism of inhibition by BW 1370U87. Decreases in urinary MHPG did not appear to be dose-dependent between 200-800 mg BW 1370U87 per day, suggesting that maximal MAO-A inhibition was achieved at the 200 mg dose. These effects on MHPG excretion may be helpful in predicting the efficacy of BW 1371370U87 in the treatment of depression. © 1993 wiley-Liss, Inc.     

Potentiation of the behavioral effects of 5-hydroxytryptophan by BW 1370U87, a selective monoamine oxidase-A inhibitor

BW 1370U87, a novel, selective, reversible monoamine oxidase-A inhibitor, was tested in the 5-HTP (5-hydroxytryptophan) potentiation test in mice and rats to establish its activity following systemic administration, to determine its duration of action and to determine if its effects were reversible in vivo. The behavioral effects of a threshold dose of 5-HTP were potentiated by BW 1370U87 in mice with ED50s of 3.4 mg/kg i.p. and 18.4 mg/kg p.o. 5-HTP potentiation occurred in rats with an ED50 of 10.4 mg/kg p.o. BW 1370U87 (20 mg/kg) was active 9 hr, but not 16 hr following oral administration, consistent with reversible enzyme inhibition.     

Biochemical and pharmacologic properties of 2614W94, a reversible,competitive inhibitor of monoamine oxidase-A

2614W94 [3-(1-trifluoromethyl)ethoxyphenoxathiin 10,10-dioxide] is a selective, reversible inhibitor of monoamine oxidase-A with a competitive mechanism of inhibition and a K_i value of 1.6 nM with serotonin as substrate. In pretreated rats, the ED₅₀ value after single oral dosing was 1.7 mg/kg, similar to an ED₅₀ value of 1.1 mg/kg estimated in the 5-hydroxytryptophan potentiation test. Maximal inhibition of monoamine oxidase-A (MAO-A) was observed by 0.5 h after dosing, suggesting rapid transport to brain. Inhibition in brain was maintained for several hours, followed by a gradual reversal with a half-time of 7.2 h. Brain levels of parent compound were higher than plasma levels at all times after dosing. No significant inhibition of MAO-B was observed. After preincubation of MAO with 2614W94 at 37°C, the inhibition was reversed by dialysis. Concentrations of serotonin, norepinephrine, and dopamine were clearly elevated in brains of rats after single oral doses, whereas levels of MAO metabolites were decreased. In a rat model designed to show blood pressure elevations in response to a threshold dose of orally administered tyramine, 2614W94 compared well with moclobemide, an MAO-A selective inhibitor that has not been associated with problems relating to dietary tyramine. The two stereoisomers of 2614W94 were both potent MAO-A inhibitors. In vitro and in vivo properties of 2614W94 suggest that this compound and its close analogs are among the most potent MAO-A inhibitors known and that they may have therapeutic potential as safe new antidepressant/anxiolytic agents. Drug Dev. Res. 45:1–9, 1998. © 1998 Wiley-Liss, Inc.     

Metabolism of BW 1370U87 by crude liver homogenates from several species: An in vitro method for preliminary investigation of species differences in metabolism

We employed broken cell liver preparations in order to investigate potential species-specific differences in the metabolism of BW 1370U87, a new selective and reversible MAO-A inhibitor. The drug metabolizing capacity of crude liver homogenates from rat, dog, cat, monkey, and man was assessed based on the utilization of BW 1370U87 and the appearance of suspected metabolites. When incubated with liver homogenates (37° C) in the presence of a cofactor preparation designed to generate TPNH, BW 1370U87 (1 or 10 μM) was metabolized in a species and time dependent manner. The rate of disappearence of BW 1370U87 was more rapid in dog and cat preparations than those of rat, monkey and man. The appearance of metabolites coincided with the disappearance of BW 1370U87. Three metabolites, identified and synthesized as BW 183U88, BW 380U88, and BW 330U88 appeared in all five species. These metabolites were also found to be selective MAO-A inhibitors both in vitro and ex vivo and may contribute to the overall activity exhibited by the parent molecule.     

Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor,TV-3326 in conscious rabbits

TV-3326 is a novel cholinesterase inhibitor that produces irreversible brain-selective inhibition of monoamine oxidase (MAO)-A and B and has antidepressant-like activity in rats after chronic oral administration. This study determined whether TV-3326 would cause less potentiation than other irreversible MAO-inhibitors of the blood pressure (BP) response to oral tyramine in conscious rabbits. Dose-response curves were established for the increase in BP induced by tyramine (5-200 mg/kg) administered orally via a naso-pharyngeal tube. From these, the dose that increased BP by 30 mmHg (ED(30)) was computed for each rabbit before and after oral administration of clorgyline, 1 mg/kg for one week, tranylcypromine 10 mg/kg, once, moclobemide, 20 mg/kg 3 times and TV-3326, 26 mg/kg for 2 weeks. Clorgyline, tranylcypromine and TV-3326 inhibited brain MAO-A by 90%; the former two inhibited intestinal MAO-A by 85-97% but TV-3326 had no effect. Tranylcypromine and clorgyline produced 6 and 20-fold increases in the pressor response to tyramine while TV-3326, like moclobemide, only potentiated it 2-fold. If TV-3326 is found to produce as little potentiation of the tyramine response in human subjects, it may be a potentially useful therapeutic agent for the treatment of Alzheimer's disease with depression.     

Ranbezolid, a novel oxazolidinone antibacterial: in vivo characterisation of monoamine oxidase inhibitory potential in conscious rats

Ranbezolid, a novel oxazolidinone antibacterial, competitively inhibits monoamine oxidase-A (MAO-A), in vitro. The consequences of MAO-A inhibition was evaluated in vivo, by testing interaction of Ranbezolid with tyramine (in solution or mixed with feed), and amine containing cold remedies on pressor response in conscious rats. Single and repeat doses of Ranbezolid (50 mg/kg, p.o.) did not affect pressor response to tyramine (5 or 15 mg/kg), but potentiated the same after a single dose of 100 mg/kg. Co-administration of Ranbezolid with tyramine in feed or with cold remedies also did not potentiate the respective pressor responses. These results suggest that Ranbezolid exhibits minimal cardiovascular liability associated with MAO-A inhibition.     

Cardiovascular sympathomimetic amine interactions in rats treated with monoamine oxidase inhibitors and the novel oxazolidinone antibiotic linezolid

Linezolid (PNU-100766) is a new gram-positive oxazolidinone antibiotic that is effective at in vitro concentrations < or =4 microg/ml and in vivo doses < or =10 mg/kg. Because linezolid also competitively inhibits human monoamine oxidase-A (MAO-A; Ki = 55 microM), we monitored its effects on the cardiovascular responses to tyramine and amine cold remedies in comparison with standard MAO inhibitors. In anesthetized rats, the pressor response to 16 microg i.v. tyramine was potentiated by the MAO-A inhibitors clorgyline (0.1-1.0 mg/kg i.v.) and moclobemide (5.0-50 mg/kg p.o.), but not by the MAO-B inhibitor selegiline (0.15-15 mg/kg p.o.). Fifteen milligrams per kilogram intravenous linezolid weakly potentiated i.v. tyramine independent of changes in alpha-adrenoceptor reactivity, but this effect was not enhanced chronically (90-100 mg/kg/day). In conscious rats, 30 mg/kg/day oral linezolid (8 microg/ml plasma concentration) minimally affected the pressor response to 20 mg/kg oral tyramine, whereas 100 mg/kg/day linezolid (20 microg/ml plasma concentration) moderately potentiated this response similar to 3 mg/kg per day moclobemide. Linezolid's tyramine potentiation was reversible, attenuated by food, and independent of pseudoephedrine, phenylpropanolamine, and dextromethorphan interactions. These studies demonstrate that high-dose linezolid only moderately potentiates the cardiovascular effects of tyramine and validate these models for evaluating such MAO inhibitory interactions.     

Effects of the delta opioid agonist BW373U86 in pigeons trained to discriminate fentanyl,bremazocine and water in a three-choice drug discrimination procedure

The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01–10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1–10 mg/kg) but not by the mu selective antagonist naloxone (0.1–30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED₅₀ values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1–1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.     

On the role of monoamine oxidase-A for the maintenance of the volitional consumption of ethanol in two different rat models

It is hypothesized that although the overall metabolism of ethanol in the brain is very limited, a very small percentage of the brain tissue may carry out that little amount of metabolism. Specifically, hydrogen peroxide may be used as a co-substrate for the metabolism of ethanol to acetaldehyde by catalase and the action of monoamine oxidase in the monoaminergic neurons would supply the hydrogen peroxide. This production of acetaldehyde may result in the formation of novel metabolites that provide the rewarding stimulus for the consumption of ethanol. To test this hypothesis, a reversible inhibitor of the A-isoform of monoamine oxidase, BW A616U, was compared to irreversible inhibitors of one or both MAO-A and B isoenzymes. Doses of 12.5-75 mg/kg p.o. BW A616U reduced the behavioral effects, ptosis and catalepsy, due to monoamine depletion by 2.5 mg/kg reserpine, but these signs of monoamine depletion were evident 24 h after injection. In the cyanamide-induced drinking rat, 50 mg/kg BW A616U reduced consumption of ethanol by 37%. Phenylzine, an irreversible MAO-A and B inhibitor, reduced consumption of ethanol by 67%, but also food consumption; however, the intake of both increased during the post-treatment period. The MAO-B inhibitor, R(-)-deprenyl, was without effect. Both BW A616U, 50 mg/kg and 75 mg/kg, and 2.0 mg/kg i.p. clorgyline reduced the consumption of ethanol in the genetic drinking Myers high-ethanol preferring (mHEP) rat and reduced the proportion of ethanol consumed to total fluids by over 50%. Again, R(-)-deprenyl was without effect. Clorgyline also markedly reduced the intake of food during the 3-day treatment period, only. However, the consumption of ethanol remained depressed during the 4 days after either 75 mg/kg BW A616U or clorgyline. These data demonstrate that inhibition of MAO-A, but not MAO-B, reduces the volitional consumption of ethanol probably by preventing the formation of both biogenic aldehydes and acetaldehyde so that rewarding alkaloidal products cannot be formed.     

The comparative influence of pyrazidol, inkazan and other antidepressant monoamine oxidase inhibitors on the pressor effect of tyramine

In experiments on conscious normotensive male Wistar rats the new antidepressants, reversible MAO-A inhibitors, pyrazidole and incazane, as well as moclobemid increased the pressor effect of orally administered tyramine. The drugs potentiated also the pressor effect of intravenous tyramine. More prolonged potentiation of tyramine action was produced by moclobemid, less prolonged by incazane. The potentiation by the studied MAO-A inhibitors of the pressor effect of tyramine reflects the inhibition of the activity of MAO-A and the first-pass metabolism of tyramine in the gut and liver, as well as the inhibition of intraneuronal MAO activity in noradrenergic nerve endings and the potentiation of sympathetic activity.     

Discriminative stimulus effects of cocaine in female versus male rats

Eight female and 8 male rats were trained to discriminate 5.6 mg/kg i.p. cocaine from saline on a 2-lever, food-reinforced drug discrimination procedure. Female rats acquired the cocaine discrimination in approximately the same number of sessions that males did (43 ± 7 vs. 51 ± 9 sessions, respectively), and the ED₅₀ for cocaine discrimination was nearly equivalent in female and male rats (2.46 ± 0.41 vs. 2.32 ± 0.49 mg/kg, respectively). The time course for cocaine discrimination was similar in female and male rats, except the offset of cocaine's effects occurred significantly earlier in females than in males. d-Amphetamine dose-dependently substituted for cocaine in all 7 males and 6 of 7 females tested, with no significant sex difference in the ED₅₀ values for d-amphetamine substitution. None of the three opioid agonists tested, morphine (μ), U69,593 (κ) or BW373U86 (δ), fully substituted for cocaine in rats of either sex. The dopamine antagonist fluphenazine blocked the discriminative stimulus effects of cocaine to approximately the same extent in both sexes. Further drug discrimination training with a higher dose of cocaine, 10 mg/kg, did not significantly alter the ED₅₀ for cocaine discrimination, and there was still no significant sex difference in ED₅₀ values (3.50 ± 0.39 vs. 2.36 ± 0.41 mg/kg in females vs. males, respectively). In these same rats, however, cocaine (1–10 mg/kg) produced significantly greater locomotor activation in females than in males on a test of spontaneous locomotor activity. Thus, these results suggest that there are few sex differences in discriminative stimulus effects of cocaine, even at doses that produce significantly different locomotor responses in female versus male rats.     

Effect of lignocaine on monoamine oxidase activity of brain and liver

In vivo administration of a single dose (100-150 mg/kg, i.p.) of lignocaine produces no change in MAO activity, while long-term treatment (50 mg/kg/day for 15 and 30 consecutive days, i.p.) produces a slight but appreciable inhibition of MAO activity with tyramine or serotonin but not with benzylamine as substrate in both rat brain and liver mitochondria. Lignocaine (2-20 mM) inhibits (in vitro) both brain and liver mitochondrial MAO activity, using tyramine, serotonin and benzylamine as substrates, in a concentration-dependent manner. Furthermore, lignocaine produces a marked in vitro inhibition of serotonin and tyramine oxidation in MAO-A and not in MAO-B preparation of rat brain. Ackermann-Potter plots of MAO indicate that lignocaine-induced inhibition of MAO activity is reversible in nature. Lineweaver-Burk plots show that lignocaine (2-10 mM) produces a significant increase in Km and decrease in Vmax of MAO for tyramine and serotonin in both brain and liver. Similarly Km and Vmax values are changed using benzylamine as substrate in the presence of relatively higher concentrations of lignocaine (5-20 mM). These results suggest that lignocaine-induced inhibition of mitochondrial membrane-bound MAO activity of both neuronal and non-neuronal tissues is associated with its conformational change.     

A novel,orally effective hypoglycemic agent,SaRI 59–801, in laboratory animals

SaRl 59-801 (59-801) (α-[dimethylaminomethyl]-2-[3-ethyl-5-methyl-4-isoxazolyl]-1H-indole-3-methanol), is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives. The 2-hr hypoglycemic ED₂₅ in fasting mice was 110 mg/kg; the plasma insulin levels were increased, with an ED₅₀ of 47 mg/kg. Significant hypoglycemic activity was observed 2 hr after oral administration of 59-801 to fasting rats (ED₂₅ = 86 mg/kg), while plasma insulin was elevated by 62% at 100 mg/kg. 59-801 caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1-hr pretreatment with 59-801 (ED₅₀ = 37 mg/kg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats. In monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mg/kg and an ED₂₅ of 33 mg/kg for a period of 6 hr after oral administration. In genetically diabetic (db⁺/db⁺) mice, 59-801 was more potent in producing hypoglycemia (ED₂₅ = 47 mg/kg) than their lean littermates (ED₂₅ = 131 mg/kg). In alloxan-diabetic rats or streptozotocin-diabetic mice, this agent was inactive at 200 mg/kg, but at 400 mg/kg, it caused reduction of blood glucose levels of 29–39 and 21%, respectively, possibly the result of stimulation of residual β-cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59-801.     

Reversible Inhibitors of Monoamine Oxidase-A (RIMAs): Robust, Reversible Inhibition of Human Brain MAO-A by CX157

Reversible inhibitors of monoamine oxidase-A (RIMA) inhibit the breakdown of three major neurotransmitters, serotonin, norepinephrine and dopamine, offering a multi-neurotransmitter strategy for the treatment of depression. CX157 (3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide) is a RIMA, which is currently in development for the treatment of major depressive disorder. We examined the degree and reversibility of the inhibition of brain monoamine oxidase-A (MAO-A) and plasma CX157 levels at different times after oral dosing to establish a dosing paradigm for future clinical efficacy studies, and to determine whether plasma CX157 levels reflect the degree of brain MAO-A inhibition. Brain MAO-A levels were measured with positron emission tomography (PET) imaging and [¹¹C]clorgyline in 15 normal men after oral dosing of CX157 (20–80 mg). PET imaging was conducted after single and repeated doses of CX157 over a 24-h time course. We found that 60 and 80 mg doses of CX157 produced a robust dose-related inhibition (47–72%) of [¹¹C]clorgyline binding to brain MAO-A at 2 h after administration and that brain MAO-A recovered completely by 24 h post drug. Plasma CX157 concentration was highly correlated with the inhibition of brain MAO-A (EC₅₀: 19.3 ng/ml). Thus, CX157 is the first agent in the RIMA class with documented reversible inhibition of human brain MAO-A, supporting its classification as a RIMA, and the first RIMA with observed plasma levels that can serve as a biomarker for the degree of brain MAO-A inhibition. These data were used to establish the dosing regimen for a current clinical efficacy trial with CX157.     

Inhibition of rat platelet 5-hydroxytryptamine uptake by chlorpyrifos and carbaryl

The organophosphate insecticide chlorpyrifos and the carbamate insecticide carbaryl were investigated in adult male rats in terms of their effects on the activity of brain monoamine oxidase-A (MAO-A) activity and on the platelet uptake of 5-hydroxytryptamine (5-HT). The activities of brain acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) were also determined. For each compound two different dosage regimens were employed. In the acute study, chlorpyrifos or carbaryl was administered at a single intraperitoneal dose of 100 mg/kg or 50 mg/kg, respectively In the subacute study, chlorpyrifos was injected at a daily dose of 20 mg/kg for 7 days, while carbaryl was given at a daily dose of 10 mg/kg for 14 days. Acute chlorpyrifos administration produced a 85.01% inhibition of AChE and a 43.4% inhibition of BuChE but had no effect on MAO-A activity and 5-HT uptake. In contrast, subacute chlorpyrifos exposure caused a 94.96% inhibition of AChE and a 85.8% inhibition of BuChE and, also, elicited a significant (35.02%) reduction in the platelet uptake of 5-HT. MAO-A activity was not affected. Acute carbaryl administration produced a 56.38% AChE inhibition and a 55.95% BuChE inhibition and also caused a significant (26.36%) decrease in 5-HT uptake but no change in MAO-A. Subacute carbaryl exposure failed to affect significantly any of the biochemical parameters determined. Interference with the 5-HT system by chlorpyrifos and carbaryl could contribute to the toxicity of these pesticides.     

Angiotensin I-converting enzyme (ACE) inhibition and antihypertensive effects of EU-5476, a new,potent, and long-acting ACE inhibitor

EU-5476 is a new, orally active angiotensin I-converting enzyme (ACE) inhibitor. In vitro, EU-5476 produced a concentration-dependent inhibition of ACE purified from rabbit lung (IC₅₀ = 0.084 μ). Inhibition showed complex kinetics and was reversible as determined by equilibrium dialysis. EU-5476 inhibited plasma ACE in mice (93.8% inhibition at 5 μmol/kg) and produced dose-dependent inhibition of plasma ACE in dogs (ID₅₀ = 2.52 μmol/kg) after oral administration. In acute aortic coarctate hypertensive rats, EU-5476 administered orally produced dose-dependent decreases in blood pressure (ED₃₀ = 0.53 μmol/kg). The magnitude and duration of blood pressure reduction in hypertensive rats were similar to those of plasma ACE inhibition in dogs, suggesting that plasma ACE inhibition per se is one of the mechanisms of the antipertensive action of EU-5476. Comparative studies showed that EU-5476, like enalapril, was more potent and longer acting than captopril in producing plasma ACE inhibition and an antihypertensive response. EU-5476 is a potent and long-acting, orally effective ACE inhibitor potentially useful in the treatment of hypertension.