Inhibition of acetylcholinesterase from Electrophorus electricus (L.) by tricyclic antidepressants

The effects of tricyclic antidepressants drugs (TCA) amitriptyline, imipramine and nortriptyline, on purified Electrophorus electricus (L.) acetylcholinesterase (AChE; acetylcholine hydrolase, EC 3.1.1.7) were studied using kinetic methods and specific fluorescent probe propidium. The antidepressants inhibited AChE activity by a non-competitive mechanism. Inhibition constants range from 200 to 400 microM. Dimethylated amitriptyline and imipramine were more potent inhibitors than the monomethylated nortriptyline. Fluorescence measurements using bis-quaternary ligand propidium were used to monitor ligand-binding properties of these cationic antidepressants to the AChE peripheral anionic site (PAS). This ligand exhibited an eight-fold fluorescence enhancement upon binding to the peripheral anionic site of AChE from E. electricus (L.) with K(D)=7 x 10(-7)M. It was observed that TCA drugs displaced propidium from the enzyme. On the basis of the displacement experiments antidepressant dissociation constants were determined. Similar values for the inhibition constants suggest that these drugs have similar affinity to the peripheral anionic site. The results also indicate that the catalytic active center of AChE does not participate in the interaction of enzyme with tricyclic antidepressants. These studies suggest that the binding site for tricyclic antidepressants is located at the peripheral anionic site of E. electricus (L.) acetylcholinesterase.     

Antiplatelet activity of the long-acting thromboxane receptor antagonist BMS 180,291 in monkeys.

The effects of the novel TxA2/prostaglandin endoperoxide (TP) receptor antagonist BMS 180,291 on platelet reactivity was determined ex vivo in conscious African green monkeys. Platelet aggregation responses to U-46,619 were decreased 50% and 100% at 23 to 24 hrs after BMS 180,291 oral doses of 1 and 3 mg/kg, respectively. In addition to inhibiting aggregation, a 3 mg/kg oral dose of BMS 180,291 also produced an 11 +/- 3-fold shift to the right in the U-46,619 concentration-response relationship for platelet shape change at 24 hrs after dosing. When the 3 mg/kg oral dose was continued for 11 days, the shift in this concentration-response relationship increased to 26 +/- 10- and 93 +/- 30-fold at 24 hrs after the 8th and 11th doses, respectively. This progressive inhibition corresponds to 93 +/- 3 and 99 +/- 1% blockade of platelet TP-receptors responsible for shape change, respectively. Comparable levels of TP-receptor blockade have been previously correlated with antithrombotic and antiischemic activities of TP-receptor antagonists in vivo. Platelet reactivity to U-46,619 had completely recovered on the 7th day after the final dose of BMS 180,291, indicating effective elimination from the circulation over this interval. In separate experiments, a 3-mg/kg i.v. dose of BMS 180,291 produced only marginal and transient hemodynamic effects in anesthetized African green monkeys. Overall, these data demonstrate that BMS 180,291 given orally once a day produces a sustained and therapeutically-relevant level of TP-receptor antagonism.     

Individual differences in effects of tricyclic antidepressants and anticholinergic drugs on operant behavior in the squirrel monkey

Tricyclic antidepressant drugs generally only decrease operant behaviors in most species studied. The present work was prompted by observations that low and moderate doses of certain tricyclic antidepressant drugs markedly increase responding under fixed-interval schedules of reinforcement in some squirrel monkeys. Amitriptyline was the most potent of the drugs studied, and nortriptyline, imipramine, chlorimipramine and desmethylimipramine produced increases at higher doses. There was an excellent correspondence between the effects of amitriptyline and those of atropine in individual subjects. The monkeys showing increases in responding with amitriptyline (0.1 – 10 mg/kg, i.m.) also showed the most marked increases with atropine (0.03 – 1.7 mg/kg, i.m.), and those showing no increases with amitriptyline also showed no increases with atropine (r = 0.95). Inter-individual differences in the effects of acutely administered tricyclic antidepressant drugs may thus be mediated by differential sensitivities of the monkeys to the antimuscarinic properties of these drugs.     

Evaluation of Systemic Antifungal Agents in X-Irradiated Mice

The effect of X irradiation on the survival time of animals experimentally infected with pathogenic fungi was studied, and the activity of antifungal agents in pre-irradiated hosts was evaluated. A 24-hr preinfection dose of X irradiation decreased the survival time of mice infected with Cryptococcus neoformans and Histoplasma capsulatum to a greater extent than Candida albicans or Blastomyces dermatitidis infections. Exposure to 400 r caused a significant reduction in the variation (S(2)) survival time of C. albicans or H. capsulatum mouse infections. A single 100-mg/kg dose of 5-fluorocytosine or amphotericin B administered within 24 hr postinfection significantly extended the survival time of mice infected with C. albicans. Delayed treatment with amphotericin B was effective against C. neoformans infections. Four 50-mg/kg doses of 5-fluorocytosine were more effective than a single 200-mg/kg dose against C. neoformans infections. A single dose of amphotericin B provided significant protection when administered 48 hr postinfection against B. dermatitidis in preirradiated mice. A single dose of saramycetin 48 hr postinfection was highly effective against H. capsulatum mouse infections. A 100-mg/kg dose of amphotericin B was only effective against this fungal pathogen when administered within 8 hr postinfection. In vivo activity of the antifungal agents studied was detected within 8 to 14 days. The relative in vivo activity of several antifungal agents indicated the importance of considering their individual pharmacological properties for optimum effectiveness. The experimental model used in this study should be useful for the detection and for the preclinical evaluation of new antifungal agents.     

Antiplatelet activity of the long-acting thromboxane receptor antagonist BMS 180,291 in monkeys

The effects of the novel TxA₂/prostaglandin endoperoxide (TP) receptor antagonist BMS 180,291 on platelet reactivity was determined ex vivo in conscious African green monkeys. Platelet aggregation responses to U-46,619 were decreased 50% and 100% at 23 to 24 hrs after BMS 180,291 oral doses of 1 and 3 mg/kg, respectively. In addition to inhibiting aggregation, a 3 mg/kg oral dose of BMS 180,291 also produced an 11±3-fold shift to the right in the U-46,619 concentration-response relationship for platelet shape change at 24 hrs after dosing. When the 3 mg/kg oral dose was continued for 11 days, the shift in this concentration-response relationship increased to 26±10- and 93±30-fold at 24 hrs after the 8th and 11th doses, respectively. This progressive inhibition corresponds to 93±3 and 99±1% blockade of platelet TP-receptors responsible for shape change, respectively. Comparable levels of TP-receptor blockade have been previously correlated with antithrombotic and antiischemic activities of TP-receptor antagonists in vivo. Platelet reactivity to U-46,619 had completely recovered on the 7th day after the final dose of BMS 180,291, indicating effective elimination from the circulation over this interval. In separate experiments, a 3-mg/kg i.v. dose of BMS 180,291 produced only marginal and transient hemodynamic effects in anesthetized African green monkeys. Overall, these data demonstrate that BMS 180,291 given orally once a day produces a sustained and therapeutically-relevant level of TP-receptor antagonism.     

Protection of red blood cell acetylcholinesterase by oral huperzine A against ex vivo soman exposure: next generation prophylaxis and sequestering of acetylcholinesterase over butyrylcholinesterase

As part of a phase Ib clinical trial to determine the tolerability and safety of the highly specific acetylcholinesterase (AChE) inhibitor huperzine A, twelve (12) healthy elderly individuals received an escalating dose regimen of huperzine A (100, 200, 300, and 400 microg doses, twice daily for a week at each dose), with three (3) individuals as controls receiving a placebo. Using the WRAIR whole blood cholinesterase assay, red blood cell AChE and plasma butyrylcholinesterase (BChE) were measured in unprocessed whole blood samples from the volunteers following each dose, and then for up to 48h following the final and highest (400 microg) dose to monitor the profile of inhibition and recovery of AChE. Significant inhibition of AChE was observed, ranging from 30-40% after 100 microg to >50% at 400 microg, and peaking 1.5h after the last dose. Gradual recovery of AChE activity then occurs, but even 48 h after the last dose red blood cell AChE was about 10% below control (pre-dose) values. Huperzine A levels in plasma peaked 1.5h after the final 400 microg dose (5.47+/-2.15 ng/mL). Plasma BChE was unaffected by huperzine A treatment (as expected). Aliquots of huperzine A-containing (from three individuals) and placebo blood samples were exposed ex vivo to the irreversible nerve agent soman (GD) for 10 min, followed by removal of unbound huperzine and soman from the blood by passing through a small C(18) reverse phase spin column. Eluted blood was diluted in buffer, and aliquots taken at various time intervals for AChE and BChE activity measurement to determine the time taken to achieve full return in activity of the free enzyme (dissociation from the active site of AChE by huperzine A), and thus the proportion of AChE that can be protected from soman exposure. Huperzine A-inhibited red blood cell (RBC) AChE activity was restored almost to the level that was initially inhibited by the drug. The increased doses of huperzine A used were well tolerated by these patients and in this ex vivo study sequestered more red blood cell AChE than has been previously demonstrated for pyridostigmine bromide (PB), indicating the potential improved prophylaxis against organophosphate (OP) poisoning.     

Antinociceptive activity of metapramine in mice. Relationship with its pharmacokinetic properties.

The antinociceptive effect of acutely and chronically (every brain elimination half-life time) administered metapramine, a tricyclic antidepressant without anticholinergic or cardiotoxic effects, was studied in three different pain tests. In the hot plate test, its action was more potent when jumping was used as a pain parameter (acute ED50 = 19 +/- 3 mg/kg, i.p.) than when pain was assessed by licking of forepaws (only 20 mg/kg, i.p. was weakly active). Five chronic doses of 15 mg/kg were as active in the tail-flick test as an acute dose of 20 mg/kg (only active dose). Metapramine was more effective in the PBQ-induced writhing test after acute (ED50 = 9.9 +/- 0.1 mg/kg, i.p.) and chronic administration. A significant linear correlation was found between the effect in this test and plasma and overall brain levels of metapramine. No correlation was observed with levels of its three desmethylated metabolites. The usefullness of using a well-defined pattern of administration based on pharmacokinetic parameters and the involvement of monoaminergic mechanisms and of some metabolites of metapramine are discussed.     

Some new carbacylamidophosphates as inhibitors of acetylcholinesterase and butyrylcholinesterase

The differences in the inhibition activity of organophosphorus agents are a manifestation of different molecular properties of the inhibitors involved in the interaction with the active site of enzyme. We were interested in comparing the inhibition potency of four known synthesized carbacylamidophosphates with the general formula RC(O)NHP(O)Cl2, constituting organophosphorus compounds, where R = CCl3 (1), CHCl2 (2), CH2Cl (3) and CF3 (4), and four new ones with the general formula RC(O)NHP(O)(R')2, where R' = morpholine and R = CCl3 (5), CHCl2 (6), CH2Cl (7), CF3 (8), on AChE and BuChE activities. In addition, in vitro activities of all eight compounds on BuChE were determined. Besides, in vivo inhibition potency of compounds 2 and 6, which had the highest inhibition potency among the tested compounds, was studied. The data demonstrated that compound 2 from the compound series 1 to 4 and compound 6 from the compound series 5 to 8 are the most sensitive as AChE and BuChE inhibitors, respectively. Comparing the IC50 values of these compounds, it was clear that the inhibition potency of these compounds for AChE are 2- to 100-fold greater than for BuChE inhibition. Comparison of the kinetics (IC50, Ki, kp, KA and KD) of AChE and BuChE inactivation by these compounds resulted in no significant difference for the measured variables except for compounds 2 and 6, which appeared to be more sensitive to AChE and BuChE by significantly higher kp and Ki values and a lower IC50 value in comparison with the other compounds. The LD50 value of compounds 2 and 6, after oral administration, and the changes of erythrocyte AChE and plasma BuChE activities in albino mice were studied. The in vivo experiments, similar to the in vitro results, showed that compound 2 is a stronger AChE and BuChE inhibitor than the other synthesized carbacylamidophosphates. Furthermore, in this study, the importance of electropositivity of the phosphorus atom, steric hindrance and leaving group specificity were reinforced as important determinants of inhibition activity.     

Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.     

Glutamyl transferase and acetylcholinesterase activity in various areas of the rat brain in alcoholic intoxication

Albino mongrel rats were used for the determination of the gamma-glutamyl transferase (gamma-GTF) and acetylcholine esterase (AChE) activities in various brain areas (cerebral hemispheres, cerebellum, hippocampus, brain stem) during acute (1.5; 4 and 6 g/kg i. p.) and chronic (15 months) alcoholic intoxication and alcohol withdrawal (24-48 h, 4 and 8 days). An increase or a decrease in the activity of these two enzymes in the various rat brain areas depends on the dose of ethanol and the time of its action. The activity of gamma-GTF grew in all brain areas during chronic ethanol intoxication; the activity of AChE was also enhanced in three brain areas but it was diminished in cerebral hemispheres. Alcohol withdrawal caused diverse changes in the activities of these two enzymes in various areas of the brain. A tendency to normalization of the gamma-GTF and AChE activities is manifested 4-8 days after alcohol withdrawal.     

Difference in the effects of the antidepressant tianeptine on dopaminergic metabolism in the prefrontal cortex and the nucleus accumbens of the rat. A voltammetric study

The effects of the new tricyclic antidepressant tianeptine were investigated on dopaminergic (DAergic) metabolism in the anteromedian prefrontal cortex and the nucleus accumbens of the rat. DAergic metabolism was assessed by the measurement of DOPAC, the main presynaptic metabolite of dopamine, using in vivo voltammetry in rats ventilated with halothane (0.5-0.75% in air). Acute treatment with tianeptine (10 mg/kg, 20 mg/kg) only increased significantly DOPAC levels in the anteromedian prefrontal cortex. After chronic treatment with tianeptine (15 days, 2 times/day) the increases in DOPAC levels in this structure were altered and less pronounced with the 20 mg/kg dose. Previous studies led to suggest that both acute and chronic effects on DAergic terminals in the anteromedian prefrontal cortex may be involved in the therapeutic action of this new antidepressant.     

Selective inhibition of acetylcholinesterase in the cerebellum and hippocampus of mice following an acute treatment with malathion

Adult male ICR mice were treated by intraperitoneal injection with 250 mg/kg of bodyweight of commercial malathion (a dose corresponding to 1/12 the LD50). After 6 h, acetylcholinesterase (AChE) activity in blood, liver, and six brain regions was determined. A statistically significant inhibition was observed in whole blood (23%), liver (21%), and, in particular, the central nervous system; the greatest degree of AChE inhibition was observed in the cerebellum (45%), followed by the hippocampus (29%). There was no significant change in AChE activity in the caudate putamen, frontal cortex, midbrain, or pons medulla. These results demonstrate that the magnitude of AChE inhibition in peripheral tissues does not accurately reflect the central-inhibitory effects of malathion on AChE activity in specific brain regions.     

Effect of dothiepin on gastric ulceration mediated by lipid derived eicosanoids

Dothiepin, a tricyclic antidepressant, significantly inhibited the development of gastric ulcers induced by alcohol, aspirin, indomethacin and Shay's pyloric ligation. Antisecretory studies in pyloric ligated rats revealed that the drug at a dose of 100 mg/kg significantly reduced total acidity, gastric output and protein content. In another set of experiments, dothiepin significantly reduced gastric output, total acidity and protein content in pyloric ligated rats which received 50% alcohol (v/v) 30 minutes after the administration of dothiepin.     

Inhibition of steroid sulphatase activity by tricyclic coumarin sulphamates

The identification of the active pharmacophore required for potent inhibition of steroid sulphatase activity, i.e. an aryl-O-sulphamate structure, has led to the synthesis and testing of a large number of 1–4 ring-based inhibitors. 4-Methylcoumarin-7-O-sulphamate (COUMATE) was one of the first non-steroid based inhibitors identified. In an attempt to increase the potency of this class of inhibitor a series of tricyclic COUMATEs (665–6615 COUMATEs) have been synthesised and evaluated. Using placental microsomes as a source of oestrone sulphatase (E1-STS) the size of the third ring of the tricyclic COUMATEs was found to have a marked effect on inhibitor potency. Whereas 665- and 6615-COUMATEs had IC₅₀s of 200 and 370 nM, respectively, the most potent inhibitor in vitro in this series was 6610 COUMATE with an IC₅₀ of 1 nM. Selected inhibitors were tested for their in vivo potency by administration of a single dose (0.1 or 1 mg/kg, p.o.) to female rats. Surprisingly, in vivo 6615 COUMATE proved to be the most active drug, inhibiting rat liver E1-STS activity by 23 and 94% when assayed 24 h after administration of the 0.1 and 1 mg/kg doses. E1-STS activity in brain tissue and white blood cells was also found to be inhibited when selected drugs were tested. These studies have identified a number of tricyclic COUMATEs with therapeutic potential.     

Direct interaction of tricyclic antidepressants with opiate binding sites in the bovine adrenal medulla

This note reports the interaction of three currently used tricyclic antidepressant drugs (clomipramine, imipramine and amitriptyline) with delta, mu and kappa opioid binding sites in the bovine adrenal medulla. Clomipramine was the only drug interacting with delta and mu sites. On the contrary, all three drugs showed a significant interactions with subtypes of the kappa binding site. Clomipramine was the most active on the kappa 2 and kappa 3 subtypes while amitriptyline showed the highest interaction with the kappa 1 subtype. On the contrary the tricyclic cyproheptadine did not present any interaction with opioid binding sites in our system. This interaction between tricyclic antidepressants and opioid binding sites might be the origin of their analgesic action.     

Protection by physostigmine against the pressor effect of soman in the rat

Intravenous injection of soman, 30 ug/kg, increased mean arterial blood pressure by 57 mmHg in urethane-anesthetized rats. The response declined slightly after a few minutes and then remained stable at about 39 mmHg for the next 20 minutes. The increase in pressure was accompanied by marked inhibition of brain acetylcholinesterase (AChE). In rats pretreated with a threshold pressor dose of physostigmine (50 ug/kg, i.v.), the peak pressor response to soman rose to the same level as that in the control group, but showed a more rapid recovery, reaching 17 mmHg at 20 minutes. The recovery of blood pressure was accompanied by partial recovery of brain AChE.     

Developmental toxicity of orally administered technical dimethoate in rats

BACKGROUND: Dimethoate (O,O-dimethyl-S-(N-methylcarbamoyl-methyl) phosphorodithioate), an organophosphate insecticide, was examined for its potential to produce developmental toxicity in rats after oral administration. METHODS: Pregnant Fischer 344 rats were given sublethal doses of 0 (corn oil), 7, 15, and 28 mg/kg/day dimethoate by gavage on gestation days (GD) 6-15. Maternal effects in 15 and 28 mg/kg/day dose groups included cholinergic signs such as tremors, diarrhea, weakness, and salivation, and depression in the maternal and fetal brain acetylcholinesterase (AChE) activities. Other maternal toxicity that included reduction in body weight and feed consumption was observed only in the treated group of 28 mg/kg/day. No maternal toxicity was apparent in the 7 mg/kg/day dose group. RESULTS: Maternal exposure to dimethoate during organogenesis significantly affected the number of live fetuses, early resorption, and mean fetal weight in the 28 mg/kg/day dose group. No external, visceral, and skeletal abnormalities were observed in any of the treated groups compared to the control. CONCLUSIONS: On the basis of the present results dimethoate can produce clinical signs of toxicity and significant inhibition of the maternal and fetal AChE activities in dose groups of 15 and 28 mg/kg/day and showed fetotoxicity without teratogenic effects at 28 mg/kg/day.     

Protective effect of quercetin in ecto-enzymes,cholinesterases, and myeloperoxidase activities in the lymphocytes of rats exposed to cadmium

The ex vivo and in vitro effects of quercetin on NTPDase, adenosine deaminase (ADA), and acetycholinesterase (AChE) activities in lymphocytes, as well as the effects of quercetin on butyrylcholinesterase (BChE) activity in serum and myeloperoxidase (MPO) activity in plasma were determined in rats. For the ex vivo experiment, animals were orally exposed to Cadmium (Cd) for 45 days. Animals were divided into eight groups: saline/ethanol, saline/Querc 5 mg/kg, saline/Querc 25 mg/kg, saline/Querc 50 mg/kg, Cd/ethanol, Cd/Querc 5 mg/kg, Cd/Querc 25 mg/kg, and Cd/Querc 50 mg/kg. The ex vivo data showed an increase in the ATP and ADP hydrolysis and ADA activity in Cd-exposed rats when compared to the control group. The treatment with quercetin 25 and 50 mg/kg prevented this increase in the ATP and ADP hydrolysis, while the treatment with quercetin 5, 25, and 50 mg/kg prevented the increase in the ADA activity. AChE, BChE, and MPO activities ex vivo presented an increase in the Cd-exposed group when compared to the control group, and the treatment with quercetin 5, 25, and 50 mg/kg prevented this increase caused by Cd exposure. The in vitro experiment showed that quercetin 5, 10, 25, or 50 µM decreased the ADA activity proportionally to the increase of the concentrations of quercetin when compared to the control group. Thus, we can suggest that the quercetin is able to modulate NTPDase, ADA, AChE, and MPO activities and contribute to maintain the levels of ATP, adenosine, and acetylcholine normal, respectively, exhibiting potent pro-inflammatory and anti-inflammatory actions.     

Dose- and duration-dependent alterations by tellurium on lipid levels: differential effects in cerebrum,cerebellum, and brain stem of mice

The effect of various doses of sodium tellurite (1/50 LD50=0.4 mg/kg, 1/25 LD50=0.8 mg/kg, and 1/10 LD50=2.0 mg/kg body weight orally) on the lipid levels (cholesterol, triglycerides, phospholipids, esterified fatty acids, gangliosides, and total lipids) in the cerebrum, cerebellum, and brainstem of male albino mice was studied after 7 and 15 d of treatment. Sodium tellurite (2.0 mg/kg body weight) for 7 d has an apparent effect on the depletion of cholesterol, triglycerides, phospholipids, esterified fatty acids, and total lipids. The cholesterol content was decreased significantly in the cerebrum, cerebellum, and brainstem after 7 d of treatment with a 2.0-mg/kg dose compared to the control. On the other hand, treatment for 15 d with doses of 0.4, 0.8, and 2.0 mg/kg body weight resulted in a significant and dose-dependent increment in cholesterol level in the cerebrum, cerebellum, and brainstem. The triglycerides content was decreased significantly in the cerebrum, cerebellum, and brainstem with the 2.0-mg/kg dose after 7 d of treatment. The doses of 0.4, 0.8, and 2.0 mg/kg orally for 15 d resulted in a significant and dose-dependent depletion of triglycerides in the cerebrum, cerebellum, and brainstem. All the doses of tellurium (0.4, 0.8, and 2.0 mg/kg) both for 7 and 15 d have depleted the level of phospholipids in varying degrees of significance in the cerebrum, cerebellum, and brainstem. However, the level of esterified fatty acids was decreased significantly with the 2.0-mg/kg dose of tellurium for 7 d but increased with the 0.4-mg/kg dose for 15 d in the cerebrum and cerebellum. The level of gangliosides was depleted in the cerebrum but elevated in the cerebellum and brainstem after receiving a 2.0-mg/kg dose of sodium tellurite for 7 d. The content of gangliosides was increased with doses of 0.4 and 0.8 mg/kg but decreased with 2.0 mg/kg for 15 d in the cerebrum, cerebellum, and brainstem. The total lipids content was depleted significantly and dose dependently after 7 and 15 d of treatment in the cerebrum, cerebellum, and brainstem. These results suggest that sodium tellurite affects the lipids content differentially in various parts of the mice brain.     

Design,synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

A novel series of chalcone derivatives (4a–8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The log P values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC₅₀: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC₅₀: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.