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In 111 rats divided into 5 groups, Ipronal (5-allyl-5-(beta-hydroxypropyl)-barbituric acid) protected rats from development of experimental ulceration of the gastric mucosa twice as effectively as diallylbarbituric acid and compound D2H (5-isopropyl-5-(beta-hydroxypropyl)-barbituric acid). Compound D1S (alpha-allophanyl-alpha-allyl-gamma-valerolactone) was devoid of this action.
A simple one-step method for the N-alkoxymethylation of barbituric acids and hydantoins is presented. The compounds are N-methoxymethylated or N-ethoxymethylated using phosphorus pentoxide and dimethoxymethane or diethoxymethane, respectively, in a chlorinated solvent. 1-Methoxymethyl-3-ethyl-5-phenylhydantoin showed significant anticonvulsant activity in the subcutaneous pentylenetetrazol test, while 1,3-bis(methoxymethyl)-5-ethyl-5-(p-tolyl) barbituric acid was inactive.
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Barbiturate-induced anesthesia is a complex mechanism that probably involves several ligand-gated ion channel superfamilies. One of these superfamilies includes the archetypical nicotinic acetylcholine receptor (nAChR), in which barbiturates act as noncompetitive antagonists. In this regard, we used the Torpedo californica nAChR and a series of barbiturate analogs to characterize the barbiturate binding site(s) on this superfamily member. [(14)C]Amobarbital binds to one high-affinity (K(d) = 3.7 microM) and several (approximately 11) low-affinity (K(d) = 930 microM) sites on the resting and desensitized nAChRs, respectively. Characteristics of the barbiturate binding site on the resting nAChR include: (1) a tight structure-activity relationship. For example, the barbiturate isobarbital [5-ethyl-5'-(2-methylbutyl) barbituric acid] is >10-fold less potent than its formula isomer amobarbital [5-ethyl-5'-(3-methylbutyl) barbituric acid] in inhibiting [(14)C]amobarbital binding. (2) A binding locus within the pore of the nAChR ion channel. Each of the barbiturate analogs inhibited the binding of [(3)H]tetracaine or photoincorporation of 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine in a mutually exclusive manner. (3) Stereoselective binding. The R(+)-enantiomers of isobarbital and pentobarbital are approximately 2-fold more potent in inhibiting 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine photoincorporation than the S(-)-enantiomers. Finally, molecular modeling suggests that within the channel, the pyrimidine ring of the barbiturate is located just above the highly conserved leucine ring (M2--9; e.g., delta Leu-265), whereas the 5' side chain projects downward, and depending upon its conformation, introduces steric hindrance to binding because of the restriction in the lumen of the channel introduced by the leucine side chains.
UNLABELLED: Neuronal nicotinic acetylcholine receptors (neuronal nAchRs) are sensitive to many anesthetics, including barbiturates, which suggests that these receptors are potential sites for anesthetic action. Subtle changes in molecular structures of the anesthetic barbiturates can produce compounds with potent convulsant activity. Whereas R(-) isomer of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) exerts anesthetic action, S(+)MPPB exhibits pure excitatory effects, including convulsion. 5-(2-cyclohexilidene-ethyl)-5-ethyl barbituric acid is another example of a convulsant barbiturate. We compared the effects of depressant and convulsant barbiturates on the neuronal nAchR-mediated current to determine whether inhibition of neuronal nAchRs contributes to the anesthetic action of barbiturates. Whole cell nicotine-induced currents were recorded in PC12 derived from rat pheochromocytoma, using the conventional whole cell patch clamp technique in the presence and absence of barbiturates. Both depressant and convulsant barbiturates inhibited the nicotine-induced inward current reversibly and in a dose-dependent manner when co-applied with nicotine. All barbiturates accelerated the current decay. There was no significant difference between the concentrations for 50% inhibition for MPPB isomers. There was no correlation between inhibition of ganglionic nAchRs and anesthetic effects of the barbiturates. These results strongly oppose the idea that inhibition of neuronal nAchRs contributes to the anesthetic action of barbiturates. IMPLICATIONS: We found that both convulsant and depressant barbiturates inhibit the current mediated through ganglionic nicotinic acetylcholine receptors in PC12 cells. This finding suggests that the inhibition of neuronal nicotinic acetylcholine receptors does not contribute to the anesthetic action of barbiturates.
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The effects of a series of barbiturates, of known and varying liver tumor-promoting ability, on several short-term endpoints including liver weight and liver-to-body weight ratio increases and induction of cytochromes(s) P-450 and epoxide hydrolase activities were examined. Male F344 rats (3 months of age) were administered barbiturates in the drinking water for 12 days. At the end of the treatment period they were killed, body and liver weights were taken, microsomal p-nitroanisole O-demethylation and epoxide hydration, and liver S-9 O-dealkylation of ethoxy-, pentoxy- and benzyloxyresorufin were measured. The latter two substrates have been shown to be preferentially metabolized by the major phenobarbital-inducible form of cytochrome(s) P-450 (P-450b), and were employed since they offered a means of differentiating more clearly varying levels of P-450 induction. Exposure to sodium barbital (SB) and sodium phenobarbital (PB) resulted in significant increases in liver weight and liver-to-body weight ratios. Induction of cytochrome(s) P-450 and epoxide hydrolase activities by the various barbiturates depended on the functional groups on C5. When ranked in terms of decreasing induction potency, the following order was obtained for each enzyme activity quantitated: PB, SB, sodium pentobarbital, amobarbital, hexobarbital and the C5-unsubstituted parent compound (barbituric acid). Thus, the barbiturates were found to exhibit a spectrum of induction potencies, with PB and SB, the most potent liver tumor promoters, yielding the greatest degree of liver weight increase and induction of cytochrome(s) P-450 and epoxide hydrolase activities.
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Amidohydrolytic reactions in oxidative pyrimidine metabolism were investigated in detail. Barbiturase has been reported to catalyze the amidohydrolysis of barbituric acid to urea and malonic acid. However, purification of the enzyme revealed that it catalyzes the ring-opening of barbituric acid to ureidomalonic acid. The existence of a consecutive enzyme named ureidomalonase, which hydrolyzes ureidomalonic acid to urea and malonic acid, was also discovered during the purification of barbiturase.
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The anticonvulsive activity of seven newly-synthesized derivatives of barbituric acid, having a hydroxylamins groups substituted in second position, with respect to convulsive agents related with the GABA-ergic transmitter system: picrotoxin, bicuculline, thiosemicarbazide and 3-mercaptopropionic acid, was studied in experiments on mice. The anticonvulsive activity of these compounds in allylglycine-induced convulsions was investigated in experiments on rats, and was compared to that of well-known drugs, such as pentobarbital, phenobarbital, allobarbital and diphenylhydantoin. The results obtained show that the hydroxylamine derivatives of barbituric acid HB-2 (2-hydroxylamino-5-ethyl-5-propylbarbituric acid) and HB-7 (2-hydroxylamino-5-ethyl-5 sec. pentylbarbituric acid) have the most pronounced anticonvulsive activity, which suggests the considerable importance of the participation of GABA-ergic transmission in the realization of this activity.
BACKGROUND: Spontaneous Ca2+ -oscillations are a possible mechanism of Ca2+ -mediated signal transduction in neurons. They develop by a periodical interplay of Ca2+, which enters the neuron from the extracellular medium and triggers Ca2+ release from the endoplasmic reticulum (ER). Ca2+ -oscillations are terminated by reuptake into the ER or plasmalemmal extrusion. Spontaneous Ca2+ -oscillations are glutamate dependent and appear to be responsible for neuronal plasticity and integration of information. Here, we examined the role of the gamma-aminobutyric acid (GABAA) receptor on spontaneous Ca2+ -oscillations and studied the effects of the anaesthetics midazolam, thiopental and the non-anesthetic barbituric acid on spontaneous Ca2+ -oscillations. METHODS: Hippocampal neuronal cell cultures of 19-day-old embryonic Wistar rats 17-18 days in culture were loaded with the Ca2+ -sensitive dye Fura-2AM. Experiments were performed using dual wave-length excitation fluorescence microscopy and calibration constants were obtained from in situ calibration. RESULTS: Spontaneous Ca2+ -oscillations are influenced by the GABAA receptor. The intravenous anaesthetics midazolam and thiopental suppressed the amplitude and frequency reversibly in a dose-dependent manner with EC50 in clinically relevant concentrations. This effect was mediated via the GABAA receptor as it could be reversed by the GABAA receptor antagonist bicuculline. In contrast, the application of barbituric acid had no effects on the spontaneous Ca2+ -oscillations. CONCLUSION: Spontaneous Ca2+ -oscillations are influenced by the GABAA receptor. Spontaneous Ca2+ -oscillations might represent an interesting model system to study anaesthetic mechanisms on neuronal information processing.
A liquid chromatographic procedure for the determination of six barbiturates (barbital, diallyl barbituric acid, phenobarbital, butabarbital, amobarbital and pentobarbital) in urine samples is described. The proposed system uses a Spherisorb octadecyl-silane ODS-2 C18 analytical column and a guard column of similar characteristics. The UV detector was set at 240 nm. A study to select adequate composition of the micellar mobile phase for the separation of these compounds in urine samples is performed. Maximum resolution was achieved with a 0.07 M sodium dodecylsulphate-0.3% propanol at pH 7.4 eluent. Limits of detection at 240 nm were ranged between 0.13 microg ml(-1) for diallyl barbituric acid and 2.7 microg ml(-1) for amobarbital. The procedure allows for the determination of these compounds in 20 minutes, it does not require prior a sample preparation step and it can be very useful to the investigation of intoxication.
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A method for the determination of therapeutic levels of barbituric acids in 25 microliter of whole blood is described. After extraction and controlled concentration of the extract to a volume of 5 microliter, the barbituric acids are N,N'-dimethylated using a microrefluxer. Of the total extract 20-100% is injected into the gas chromatograph. Low blanks, recoveries of 70--80% and peak ratios that are comparable to those in calibration experiments are obtained provided the detailed working instructions are followed strictly. In addition, barbiturates were determined (1 ng in 25 microliter blood) using column-switching devices and nitrogen-sensitive detection.