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PubMed1991

Inhibition of adenylate cyclase by p-bromophenacyl bromide.

p-Bromophenacyl bromide (BPB) is an alkylating agent which has been used in biochemical studies as an inhibitor of phospholipase A2 activity. We report here that BPB irreversibly inhibited adenylate cyclase activity stimulated by hormones, forskolin, GppNHp, NaF, and cholera toxin. The action of BPB in S49 lymphoma cell membranes (wild type and cyc-) indicates that it can inhibit adenylate cyclase function in the absence of Gs. In the presence of Gs, however, inhibition of adenylate cyclase by BPB was enhanced, suggesting that BPB may covalently modify the catalytic protein on a site involved in activated catalytic functioning or critical to its interaction with Gs and/or additionally on the alpha s protein.

Acetophenones↗
PubMed1993

Inhibition of phospholipase A2 purified from human herniated disc.

The effect on human herniated intervertebral disc phospholipase A2 (HD-PLA2) of a number of retinoids, antirheumatic drugs and reported PLA2 inhibitors was evaluated using autoclaved [1-14C]-oleate-labeled Escherichia coli membranes as the substrate. Dexamethasone, non-steroidal antiinflammatory drugs, aristolochic acid and retinol were inactive, whereas a marked inhibition was found for manoalide, retinal, nordihydroguaiaretic acid and p-bromophenacyl bromide after preincubation with the enzyme (IC50 values 0.25, 4, 5 and 5 microM, respectively). The results are parallel to those obtained with the PLA2 purified from human synovial fluid.

Acetophenones↗
PubMed1993

Interindividual variability of carbonyl reductase levels in human livers.

Interindividual variability of carbonyl reductase levels in human livers (N = 11) was examined by measuring reductase activity toward various substrates and by western blot analysis using anti-rat ovarian carbonyl reductase CR2 antibody. The carbonyl reductase activity toward p-nitrobenzaldehyde (PNBA) (58.1 +/- 5.4 nmol/mg protein/min, mean +/- SE) was highest among the substrates examined, followed by 4-benzoylpyridine (4BP) (14.4 +/- 2.0 nmol/mg protein/min) and p-nitroacetophenone (PNAP) (2.00 +/- 0.37 nmol/mg protein/min). The reductase activity (6.33 +/- 0.56 pmol/mg protein/min) toward 13,14-dihydro-15-keto-prostaglandin F2 alpha (15KD-PGF2 alpha), which is a diagnostic substrate for rat ovarian carbonyl reductases, was relatively high compared to that in other species. Western blot analysis revealed that each human liver contained several immunoreactive proteins to anti-CR2 antibody. The activities toward 15KD-PGF2 alpha (r = 0.85, P < 0.01) and 4BP (r = 0.84, P < 0.01), but not PNBA (r = 0.53, not significant) or PNAP (r = 0.52, not significant), were closely correlated with the relative amounts of the high molecular weight immunoreactive proteins determined with a densitometer. Thus, the major carbonyl reductases in human liver are similar to those of rat ovarian enzymes.

Acetophenones↗
PubMed1985

Inhibition of nicotinic receptor mediated ion fluxes in rat sympathetic ganglia by BGT II-S1 a potent phospholipase.

The mechanism of action of the bungarotoxin fraction II-S1 (BGT II-S1), which copurifies with alpha-bungarotoxin (alpha-BGT) and inhibits nicotinic transmission, has been further characterized. BGT II-S1 (1 microM) inhibited the carbachol (100 microM) or nicotine (50 microM) stimulated uptake of [3H]agmatine into rat sympathetic ganglia by 73% and 52%, respectively. These responses were inhibited 90% by D-tubocurarine (100 microM), but unaffected by alpha-BGT (1 microM) or atropine (10 microM), suggesting that BGT II-S1 affects nicotinic function at a postsynaptic site. Binding of physiologically active [125I]BGT II-S1 could be demonstrated to intact sympathetic ganglia; however, the binding could not be displaced by nicotinic agents, suggesting that BGT II-S1 is not interacting at the receptor. Because some neurotoxins produce their effect at the synapse through a phospholytic action, the phospholipase activity of BGT II-S1 was determined. The results demonstrate that BGT II-S1 is a very potent calcium dependent phospholipase. In addition, conditions which abolished the toxin's phospholytic activity prevented its effects on nicotinic transmission and on nicotinic receptor mediated ion fluxes. These include irreversible inhibition of enzymic activity by treatment of BGT II-S1 with p-bromophenacylbromide, as well as reversible inhibition of the phospholipase by substitution of Ba2+ or Sr2+ ions for Ca2+ ions in the physiological medium. Thus, in rat sympathetic ganglia, BGT II-S1 blocks the nicotinic receptor mediated movement of ions across the membrane. This is probably not due to a direct interaction at the nicotinic acetylcholine recognition site; rather, it may be an ion channel associated effect which is mediated by alterations in the phospholipid environment of the receptor complex or of the membrane. Although BGT II-S1 also has presynaptic actions, in a cultured system of postsynaptic cells, it could prove a useful tool to study the role of phospholipids in neuronal nicotinic receptor regulation.

Acetophenones↗
PubMed1990

Effect of bromophenacyl bromide, a phospholipase A2 inhibitor, on the induction and maintenance of LTP in hippocampal slices.

The effect of bromophenacyl bromide (BPB), a phospholipase A2 (PLA2) inhibitor, on both the induction and the maintenance of long-term potentiation (LTP) was investigated in field CA1 of the hippocampal slice preparation. One hour of BPB application (50 microM) caused a large reduction in the magnitude of LTP induced by a theta burst stimulation (TBS) paradigm. BPB had no significant effect on either the degree of paired-pulse facilitation or the amount of pre-established LTP. Furthermore, the facilitation of postsynaptic responses occurring during TBS and in the first minute following TBS was not reduced by the PLA2 inhibitor. These results indicate that the inhibition of LTP produced by BPB is not due to an effect of the drug on a physiological event that triggers LTP. The data also suggest that PLA2 activation plays a critical role in the expression of LTP, but is not required for the maintenance of the potentiation.

Acetophenones↗
PubMed1990

Arachidonic acid metabolites do not mediate modulation of neurotransmitter release by adenosine in rat hippocampus or striatum.

The possible involvement of arachidonic acid metabolites as mediators of the modulation of neurotransmitter release by adenosine, acetylcholine, and GABA was examined in brain slices of rat hippocampus and striatum. The synaptic modulatory effects of these 3 agents on excitatory transmission in the CA1 region of hippocampus were completely unaffected by a phospholipase inhibitor (p-bromophenacyl bromide, BPB; 10-50 microM), a lipoxygenase inhibitor (nordihydroguaiaretic acid; 5-50 microM), the cyclooxygenase inhibitor indomethacin (10-20 microM), and a cyclooxygenase/lipoxygenase inhibitor (U53059; 5-10 microM). BPB was also found to be ineffective in altering the modulation of transmission by adenosine in the perforant path, and the adenosine inhibition of electrically stimulated release of endogenous dopamine from striatal slices. Arachidonic acid itself also had no effect on synaptic transmission. While these experiments do not rule out such a role for arachidonic acid or its metabolites in mammalian brain, they suggest that in a number of systems the inhibition of transmitter release must occur through an entirely independent mechanism.

Acetophenones↗
PubMed1993

The phospholipase A2 inhibitor bromophenacyl bromide prevents the depolarization-induced increase in [3H]AMPA binding in rat brain synaptoneurosomes.

We previously demonstrated that potassium (KCl)-induced depolarization of synaptoneurosomes prepared from rat telencephalon increased [3H]amino-3-hydroxy-5-methylisoxazole-4-propionate ([3H]AMPA) binding to the AMPA receptor. In the present study, we determined the effects of inhibitors of various calcium-dependent enzymes on this response to depolarization. Treatment of intact synaptoneurosomes with the phospholipase A2 (PLA2) inhibitor, bromophenacyl bromide (BPB), produced a marked and dose-dependent reduction in KCl-induced enhancement in [3H]AMPA binding. BPB had no significant effect on [3H]TPP accumulation in intact synaptoneurosomes, an index of membrane depolarization. In contrast to BPB, inhibitors of calcium-dependent kinases and proteases did not reduced the KCl-induced increase in [3H]AMPA binding. The results strengthen the hypothesis that phospholipase-induced modifications of AMPA receptor properties may be an important component of synaptic plasticity.

Acetophenones↗
PubMed1996

Norepinephrine transmitter metabolite is a selective cell death messenger in differentiated rat pheochromocytoma cells.

3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL) is the monoamine oxidase A (MAO-A) metabolite of norepinephrine (NE) and epinephrine (Epi). Oxidative metabolites of amines are predicted toxins. In this study we determine the toxicity of DOPEGAL, its tautomer 2',3,4-trihydroxyacetophenone (THAP) as well as NE, Epi and their oxidative and methylated metabolites in cultures of differentiated PC-12 cells. At 59.5 microM DOPEGAL, THAP and Epi, but not NE or other NE or Epi metabolites decreased PC-12 cells by 43.8%, 26.7% and 16.8% respectively. DOPEGAL toxicity was concentration and time dependent. Possible implications for degenerative diseases are discussed.

Acetophenones↗
PubMed1996

GABAA receptor alpha 1-subunit-immunopositive neurons in the rat striatum.

The morphological characteristics and distribution of striatal neurons expressing the GABAA receptor alpha 1-subunit were investigated following immunolabeling with an alpha 1-subunit-specific antibody. alpha 1-Immunopositive striatal neurons are relatively scarce. Those located in the dorsal striatum are small and have rounded somata and numerous dendrite varicosities. alpha 1-Immunoreactive neurons with these characteristics were likewise observed in the ventral striatum, which also contained large pyramidal neurons with smooth dendrites and polygonal neurons with spiny dendrites. A fourth neuron type (oval neurons with dendrites oriented in bipolar fashion) was found in the lateral striatum. All four neuron types were observed in the rostral, central and caudal striatum. Double-labeling experiments using an antibody specific for DARPP-32 (a cell-level indicator of dopamine D1-like receptors) and the alpha 1 antibody showed a complete lack of colocalization of these two markers in striatal neurons.

Acetophenones↗
PubMed1996

Involvement of the 12-lipoxygenase pathway of arachidonic acid metabolism in homosynaptic long-term depression of the rat hippocampus.

Low-frequency stimulation is associated with long-term depression (LTD) of synaptic efficacy in various brain structures. Like long-term potentiation (LTP), homosynaptic LTD in area CA1 of the hippocampus appears to require NMDA receptor activation, changes in postsynaptic calcium concentration and phospholipase A2 (PLA2) activation. Arachidonic acid (AA) is released after the activation of calcium-dependent phospholipases and free AA is rapidly metabolized to a family of bioactive products (the eicosanoids) which are thought to be both intracellular and extracellular messengers. In the present study, we investigated the involvement of the cyclooxygenase and lipoxygenase pathways of AA metabolism in the formation of homosynaptic LTD in the rat hippocampus. Stimulation at 1 Hz for 15 min was used to produce homosynaptic depression in area CA1 of hippocampal slices. LTD induction was partially blocked by bromophenacyl bromide (50-100 microM), a selective PLA2 inhibitor, and by the a nonselective lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 100 microM). In contrast, the specific cyclooxygenase blocker indomethacin (100 microM) did not significantly reduce hippocampal LTD. Since NDGA interferes with LTD formation, we examined whether specific inhibitors of 5- and 12-lipoxygenases were capable of blocking LTD expression. The 12-lipoxygenase inhibitor baicalein at a concentration of 50 microM reduced LTP formation when given in the bath, an effect that was less pronounced with the 5-lipoxygenase inhibitor AA-861. These data suggest that the activation of endogenous PLA2 and the formation of 12-lipoxygenase metabolites of AA may be important factors controlling the expression of hippocampal LTD.

Acetophenones↗
PubMed1984

Assessment of a role for phospholipase A2 and arachidonic acid metabolism in human lymphocyte natural cytotoxicity.

The reagents quinacrine, hydrocortisone, and dexamethasone have been assumed to affect phospholipase A2 (PA2) when they reduce natural killer (NK) activity. However, these reagents did not reduce lymphocyte incorporation of [14C]arachidonate, which implies that they are not acting as PA2 inhibitors in this lymphocyte system. However, p-bromophenacyl bromide (BPB), which is an active site inhibitor of PA2, irreversibly abrogated NK activity of pretreated lymphocytes, disrupted target cell binding, and reduced [14C]arachidonic acid incorporation by 70-80% as compared to controls. Other observations contrary to expectations for PA2 inhibitors were: (1) quinacrine inhibited NK lysis when lymphocytes were pretreated and (2) the glucocorticoids only inhibited NK activity when continuously present in the assay. Furthermore, NK inhibition by hydrocortisone did not require protein synthesis. The lipoxygenase inhibitors, nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosotetraynoic acid (ETYA), and hydroxyphenylretinamide, and not cycloxygenase inhibitors, reduced NK activity. These data suggest that arachidonate must be metabolized through the 5-lipoxygenase pathway in order to function in NK.

Acetophenones↗
PubMed1993

Determination of acylcarnitines in urine of patients with inborn errors of metabolism using high-performance liquid chromatography after derivatization with 4'-bromophenacylbromide.

A high-performance liquid chromatographic method is presented for the determination of urinary acylcarnitines. After solid phase extraction on silica columns the acylcarnitines are converted to 4'-bromophenacyl esters with 4'-bromophenacylbromide in the presence of N,N-diisopropylethylamine. Complete derivatization was achieved at 37 degrees C within 30 min. The 4'-bromophenacyl esters were separated by high-performance liquid chromatography on a Hypersil BDS C8 reversed-phase column with a binary gradient containing varying proportions of acetonitrile, water and 0.1 M triethylamine phosphate buffer. Essentially baseline separation was obtained with a standard mixture containing 4'-bromophenacyl esters of carnitine and synthetic acylcarnitines of increasing chain length ranging from acetyl- to palmitoylcarnitine. The method was used to obtain urinary acylcarnitine profiles from patients with propionic, methylmalonic and isovaleric acidemia and with medium-chain and multiple acyl-CoA dehydrogenase deficiency. Quantification of the acylcarnitines was achieved using undecanoylcarnitine as internal standard.

Acetophenones↗
PubMed1995

Acetylcholinesterase inhibition by zifrosilone: pharmacokinetics and pharmacodynamics.

OBJECTIVE: To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. METHODS: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, with four subjects receiving zifrosilone (10, 30, 60, 90, 120, 150, 200, 250, and 300 mg orally) and two subjects receiving matching placebo. Serial blood samples were obtained for zifrosilone plasma concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening. RESULTS: A greater than proportionate increase in mean plasma concentration values for area under the curve from time zero to infinity was observed over the 200 to 300 mg dose range groups. Red blood cell acetylcholinesterase showed a dose-inhibition relationship, with a mean maximum inhibition of 20.9% at 10 mg that increased to 62.1% at 300 mg. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (< 20% inhibition at 300 mg). For doses > or = 200 mg, an Emax pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (Emax = 83.8%; EC50 = 0.65 ng/ml). CONCLUSIONS: Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.

Acetophenones↗
PubMed1976

Role of dopamine in the anorexigenic effect of DITA; comparison with d-amphetamine.

The effects of d,1-alpha-methyltyrosine (alphaMT), haloperidol, phenoxybenazmine, propranolol, methysergide and cyproheptadine on the anorexigenic activities of DITA and d-amphetamine were studied in male mice. The pretreatment of mice with methysergide (10 mg/kg, s.c.), cyproheptadine (5 mg/kg, i.p.), phenoxybenzamine (10 mg/kg, i.p.), and propranolol (5 mg/kg, i.p.) failed to alter the anorexigenic effect of DITA and d-amphetamine. On the other hand, alphaMT (32 mg/kg, i.p.) and haloperidol (0.5 mg/kg, i.p.) significantly antagonized the anorexigenic effect of DITA and d-amphetamine. Our data indicate that the anorexigenic activities of DITA and d-amphetamine are mediated mainly through the dopaminergic system.

Acetophenones↗
PubMed1977

Antiarrhythmic and electrophysiological effects of CH-200.

A new antiarrhythmic drug CH-200, 5-phenacyl-thieno[3,2-c]yridinium, was compared with procainamide and lidocaine in a two-stage coronary ligation arrhythmia model for its efficacy and electrophysiological properties. CH-200 suppressed arrhythmia in beagle dogs more effectively than did procainamide and lidocaine. The antiarrhythmic effects of CH-200 and procainamide developed slowly and lasted longer than those of lidocaine. Electrophysiological studies with CH-200 showed that it decreased max dV/dt of the action potential. This effect was dependent on the heart rate: the higher the rate, the stronger the effect. CH-200, procainamide and lidocaine prolonged the effective refractory period and this effect seemed to be responsible for suppressing the arrhythmia after coronary ligation. CH-200 and procainamide increased the frequency of ventricular pacemaker activity, while lidocaine decreased it. These effects appear to be unimportant for the antiarrhythmic effects.

Acetophenones↗