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PubMed1993

5-Benzylbarbituric acid derivatives, potent and specific inhibitors of uridine phosphorylase.

5-Benzylbarbituric acid derivatives were synthesized as a series of new, specific, and potent inhibitors of uridine phosphorylase. Among these, 5-(m-benzyloxy)benzyl-1-[(2-hydroxyethoxy)methyl] barbituric acid (5-benzyloxybenzylbarbituric acid acyclonucleoside, BBBA) was found to be the most potent with Ki values of 1.1 +/- 0.2 and 2.6 +/- 0.3 nM with uridine phosphorylase from human and mouse livers, respectively. BBBA exhibited competitive inhibition with uridine phosphorylase from both human and mouse livers. The 5-benzylbarbituric acid derivatives are specific inhibitors of uridine phosphorylase, as they had no effect on thymidine phosphorylase (EC 2.4.2.4), thymidine kinase (EC 2.7.1.21), uridine-cytidine kinase (EC 2.7.1.48), orotate phosphoribosyltransferase (EC 2.4.2.10), orotidine 5'-monophosphate decarboxylase (EC 4.1.2.23), and dihydrouracil dehydrogenase (EC 1.3.1.2). These compounds are more potent, easier to synthesize, and have better water solubility than their uracil counterparts as inhibitors of uridine phosphorylase. Furthermore, the 5-benzylbarbituric acids were found to be better inhibitors of human uridine phosphorylase than the murine enzyme, whereas the reverse holds true for the 5-benzyluracil derivatives. The 5-benzylbarbituric acid derivatives have potential usefulness in the therapy of cancer and AIDS, as well as other pathological and physiological disorders.

Animals↗

PubMed1985

Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes.

The effects of several anticonvulsant drugs on sodium-dependent high affinity choline uptake (HACU) in mouse hippocampal synaptosomes was investigated. HACU was measured in vitro after in vivo administration of the drug to mice. HACU was inhibited by drugs which have in common the ability to facilitate gamma-aminobutyric acid (GABA) transmission, pentobarbitone, phenobarbitone, barbitone, diazepam, chloridiazepoxide, and valproic acid. Dose-response relationships were determined for these drugs and the drugs' potencies at inhibiting HACU correlated well with their anticonvulsant potencies. Clonazepam, ethosuximide, carbamazepine, and barbituric acid had no effect on HACU in the doses used while phenytoin and trimethadione stimulated HACU. These results suggest that certain anticonvulsants may elicit a part of their anticonvulsant activity by modulating cholinergic neurones. This effect may be mediated through a GABA mechanism.

Animals↗

PubMed2000

Legumes-whey weaning food: storage studies.

Legume-whey weaning foods formulas were stored for 6 months in aluminum foil coated by polyester at room temperature (22-25 degrees C) and refrigerator (4 degrees C). Peroxide values and free fatty acids values of weaning food formulas reached to its maximum after 3 and 2 months, respectively, and after that continuously decreased during storage. Thio-barbituric acid values of all samples increased gradually throughout the storage period at different condition of storage (room temperature and refrigerator). The protein in-vitro digestibility of all samples was not affected during storage. Protein solubility index in distilled water, 5% NaCl and 5% sucrose decreased with different obvious rates, but bulk density of weaning food formula decreased within a very narrow ranges during storage period. Total bacterial counts as well as yeast and molds decreased gradually throughout the storage period at different conditions of storage, and cold stored samples became free from molds and yeast after 6 months of storage.

Dairy Products↗

PubMed1999

Pyrimidine nucleobase ligands of orotate phosphoribosyltransferase from Toxoplasma gondii.

Sixty-seven pyrimidine nucleobase analogues were evaluated as ligands of Toxoplasma gondii orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) by measuring their ability to inhibit this enzyme in vitro. Apparent Ki values were determined for compounds that inhibited T. gondii OPRTase by greater than 20% at a concentration of 400 microM. 1-Deazaorotic acid (0.47 microM) and 5-azaorotic acid (2.1 microM) were found to bind better (8.3- and 1.9-fold, respectively) to T. gondii OPRTase than orotic acid, the natural substrate of the enzyme. Based on these results, a structure-activity relationship of ligand binding to OPRTase was formulated using uracil, barbituric acid, and orotic acid as reference compounds. It was concluded that the following structural features of pyrimidine nucleobase analogues were required or strongly preferred for binding: (i) an endocyclic pyridine-type nitrogen or methine at the 1-position; (ii) exocyclic oxo groups at the 2- and 4-positions; (iii) a protonated endocyclic pyridine-type nitrogen at the 3-position; (iv) an endocyclic pyridine-type nitrogen or methine at the 5-position; (v) an exocyclic hydrogen or fluorine at the 5-position; (vi) an endocyclic pyridine-type nitrogen or methine at the 6-position; and (vii) an exocyclic negatively charged or electron-withdrawing group at the 6-position. A comparison of the results from the present study with those from a previous study on mammalian OPRTase [Niedzwicki et al., Biochem Pharmacol 33: 2383-2395, 1984] identified four compounds (6-chlorouracil, 5-azaorotic acid, 1-deazaorotic acid, and 6-iodouracil) that may bind selectively to T. gondii OPRTase.

Animals↗

PubMed1985

Dissociation of [35S]t-butylbicyclophosphorothionate binding differentiates convulsant and depressant drugs that modulate GABAergic transmission.

The dissociation of [35S]t-butylbicyclophosphorothionate ([35S]TBPT) from binding sites on membranes from rat cerebral cortex, after addition of saturating concentrations of convulsant and depressant drugs, was studied. The addition of unlabeled TBPT, picrotoxinin, or pentamethylenetetrazol resulted in dissociation patterns that were monophasic and not distinguishable, suggesting that these convulsants bind competitively to the same (convulsant) sites. In contrast, gamma-aminobutyric acid (GABA) greatly facilitated [35S]TBPT dissociation by binding allosterically to the GABA recognition site of the receptor-ionophore complex. TBPT dissociation was similarly accelerated by the depressants etazolate, (+)-etomidate, and barbiturates. The convulsant and depressant S(+) and R(-) stereoisomers of N-methyl-5-phenyl-5-propyl-barbituric acid displayed large stereoselectivity in the acceleration of TBPT dissociation. These results suggest that depressants bind to sites different from the convulsant sites of the allosteric GABA receptor complex, or the binding of depressants to the same population of sites elicits negative cooperativity and dissociates the convulsants.

Animals↗

PubMed1977

Uracil metabolism in golden hamster after irradiation.

The catabolism of uracil and the total balance of excreted radioactivity were studied in golden hamsters after a peroral application of 14C-uracil. Twenty-four hours after administration most of the radioactivity taken up appeared in expired carbon dioxide. The percent proportion of radioactivity in carbon dioxide was independent of the amount of uracil administered. On the other hand, the percentage of radioactivity excreted in urine depended on the amount of uracil taken up, high doses of the compound causing up to eight-fold increase in urine-excreted radioactivity. Most of the exogenously-administered uracil was catabolized within the first 5 hours. Irradiation had no substantial effect on the dynamics of uracil catabolism. Analysis of urine revealed that most urine-excreted radioactivity is in the form of uracil. On peroral application of high doses of uracil to irradiated hamsters, their urine was found to contain barbituric acid which originated from uracil.

Animals↗

PubMed1988

Circadian characteristics of dialyzable and non-dialyzable human urinary electrolytes, trace elements and total solids.

Seven clinically-healthy men ranging in age from 21 to 25 years participated in this study. Urine samples were collected at 3 hr intervals over a single 24 hr span. Urines were pooled by using 20% of the total volume collected from each subject over a 3 hr collection span. The resulting 8 pools were analyzed for pH, specific gravity, osmolality, urea N, creatine, uric acid, glucose, phosphorus, chlorides, sodium, potassium, calcium, magnesium, silicon, aluminum, zinc and total solids. Each of the 8 pools was serially dialyzed at pH 7.35 against ammonium-barbituric acid buffer. The non-dialyzable portions were then re-analyzed for the remaining solids, sodium, potassium, calcium, magnesium, silicon, aluminum and zinc. Aliquots of the non-dialyzable fraction were examined by high performance liquid chromatography. Up to twelve discernable fractions were observed in each 3 hr urine by monitoring ultraviolet light absorbance at 280 nm wavelength. Range of change throughout the 24 hr (lowest to highest value) for most variables was 100% or more. In the eight 3 hr pooled urine samples, statistically-significant circadian variation could be described for volume, pH, osmolality, urea nitrogen, creatinine, uric acid, glucose, phosphorus, chlorides, for five of eight non-dialyzed (total) components (Na, K, Ca, Si and solids) and for five of twelve non-dialyzable solid fractions, as well as for total non-dialyzable solids. Single cosinor analysis resulted in description of a significant circadian rhythm in osmolality, urea nitrogen, creatinine, glucose, phosphorus, chlorides, total Na, K, Si and solids; non-dialyzable Si and solids; dialyzable Na, K, Si and solids; and for total solids, as well as their fractions at 23.4 and 25.9 min. These observations are furnished in order to further document the extreme circadian rhythmicity in all aspects of kidney function and as reference for future work which uses any of the investigated urinary endpoints whose circadian time structure is herein described.

Adult↗

PubMed1989

[Studies on visible-light initiator system using thiobarbituric acid derivatives].

Experimental visible-light curing resins were prepared by the combination of dl-camphorquinone and a thiobarbituric acid derivative, such as 5-methyl-2-thiobarbituric acid (5 MS), 5-n-butyl-2-thiobarbituric acid (5 BS), and 1,3,5-trimethyl-2-thiobarbituric acid (135 MS). The ability of their initiator systems to polymerize resins was investigated and was also compared with that of initiator systems containing 5-n-butyl-barbituric acid (5 B) or N,N-dimethylaminoethyl methacrylate (DMAEMA) as the most popular reducing agent. The amount of insufficiently polymerized layer was small in 135 MS at a low concentration, and in DMAEMA at a high concentration, respectively. 135 MS was superior to DMAEMA in curing time, maximum exothermic rate and depth of cure at a concentration of 1.0 mole%. 135 MS, therefore, seemed comparable or superior to DMAEMA. The order of increasing activity as a reducing agent was 5 BS less than 5 MS less than DMAEMA less than or equal to 135 MS. When analogous 5 B and 5 BS were compared, the sulfur-containing 5 BS was more effective as a reducing agent.

Acrylic Resins↗

PubMed1996

Thermodynamics and kinetics of t-butylbicyclophosphorothionate binding differentiate convulsant and depressant barbiturate stereoisomers acting via GABAA ionophores.

The temperature dependence of [35S]-t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites of the GABAA receptor complex was studied in membrane preparations of rat forebrain. Although specific [35S]TBPS binding was maximal around 20 degrees C, the rate constants of dissociation decreased monotonously between 37 degrees C and 2 degrees C. The displacing potencies of the convulsant S(+) enantiomer of 1-methyl-5-phenyl-5-propyl-barbituric acid (MPPB) (IC50 = 1250 +/- 30 microM) and the depressant R(-) MPPB (IC50 = 310 +/- 5 microM) did not show significant changes between 19 degrees C and 37 degrees C. Therefore barbiturate binding seems to be driven by entropic, rather than enthalpic changes. An excess of MPPB enantiomers elicited accelerated and polyphasic dissociations of [35S]TBPS as compared to the monophasic dissociation by TBPS. Arrhenius analysis was applied to the measurable initial rate constants of dissociation. Arrhenius plots were linear between 2 degrees C and 37 degrees C. Activation parameters were similar when [35S] TBPS dissociation was triggered by the convulsants TBPS and S(+) MPPB. It can be attributed to similar conformations of the closed ionophore complex. In contrast, the depressant R(-) MPPB strongly decreased the activation energy of TBPS dissociation from the open ionophore ternary complex. In whole-cell patch-clamp experiments R(-) MPPB, but not S(+) MPPB, elicited chloride currents in rat primary cortical cultures with an EC50 value of 560 +/- 30 microM and a Hill coefficient of 2.9 +/- 0.2. These currents were similar to those elicited by GABA and blocked by TBPS. A kinetic scheme is proposed for the dissociation of TBPS and to explain the different effects of MPPB enantiomers. Submillimolar R(-) MPPB is supposed to bind to (about three) barbiturate sites on GABAA-ionophores and to open them in a cooperative manner to result in a decreased activation energy for accelerated displacement of convulsant binding.

Animals↗

PubMed1984

Interaction of barbiturates with adenosine receptors in rat brain.

The effects of barbiturates on radioligand binding to inhibitory Ri adenosine receptors of rat brain membranes were investigated. Binding of the adenosine receptor agonist (-)N6-phenylisopropyl[3H]adenosine and the antagonist 1,3-diethyl-8-[3H]phenylxanthine was inhibited by several barbiturates. This inhibition was concentration-dependent and occurred in the range of pharmacologically effective concentrations. Pentobarbital was the most potent of the barbiturates tested with a Ki of 92 mumol/l. The (+)isomers of hexobarbital and mephobarbital were more potent than the respective (-)isomers. Barbituric acid itself did not displace either radioligand in concentrations up to 1 mmol/l. The inhibitory effect of pentobarbital was reversed by a single wash of membranes preincubated with the barbiturate. The presence of pentobarbital caused a decrease of the affinity of the receptor for the antagonist radioligand but did not alter the number of binding sites, suggesting a competitive antagonism. The effects of pentobarbital on radioligand binding to the receptor were not changed by the presence of picrotoxinin nor by the absence of chloride ions. This indicates that they are not mediated via the picrotoxinin binding site. The barbiturates could not be classified as either agonists or antagonists at the Ri adenosine receptor. The presence of GTP did not influence the inhibition of radioligand binding by pentobarbital; this is also observed for antagonists, whereas the affinity of agonists is markedly reduced by GTP. Binding of antagonists to the receptor is enthalpy-driven; the interaction of pentobarbital with the receptor was entropy-driven and the same was true for agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed2001

Selenomethionine substitution of orotidine-5'-monophosphate decarboxylase causes a change in crystal contacts and space group.

Orotidine 5'-monophosphate decarboxylase (ODCase) catalyses the decarboxylation of orotidine 5'-monophosphate to uridine 5'-monophosphate, the last step in the de novo biosynthesis of uridine 5'-monophosphate. In order to determine the structure of ODCase from Escherichia coli by the multi-wavelength anomalous dispersion technique, both native and SeMet-substituted proteins have been produced and purified. During the production of SeMet ODCase, it was observed that SeMet was the only amino acid that it was necessary to add to the defined medium during expression. SeMet-substituted ODCase in complex with the inhibitor 1-(5'-phospho-beta-D-ribofuranosyl)barbituric acid crystallizes under similar conditions as the native enzyme. In contrast to the native enzyme, where the crystals belong to the orthorhombic space group P2(1)2(1)2(1), the SeMet-substituted enzyme crystallizes in the monoclinic space group P2(1), with a quadrupling of the volume of the asymmetric unit. Despite the drastic difference in symmetry, the overall crystal packing is effectively identical in the two crystal forms. The change in space group appears to originate in differences in the crystal contacts near the SeMet and Met residues. These differences can be rationalized in terms of SeMet's larger size and hydrophobicity.

Amino Acid Substitution↗

PubMed1994

Merocyanine dyes: effect of structural modifications on photophysical properties and biological activity.

Merocyanine derivatives were prepared by structural alterations at the barbituric acid or chalcogenazole moieties. The photophysical properties of the dyes were markedly influenced by the presence of selenium rather than sulfur as a substituent at position 2 of the barbiturate. In methanol, quantum yields of both triplet state (phi T) and singlet oxygen sensitization (phi delta) were increased by over an order of magnitude, with a concomitant decrease in fluorescence, when selenium was present in the molecule. Photoisomerization, one of the dominant deactivation pathways in the sulfur- or oxygen-containing analogues, was completely absent in the selenium-containing derivatives. Efficient triplet state formation was observed for selenium-containing derivatives incorporated into L1210 cells by diffuse reflectance laser flash photolysis. Cytotoxicity studies, carried out using clonogenic assays on L1210 leukemia cells, showed a good correlation with phi T and phi delta, measured in solution. Experimental evidence provided by this paper supports a triplet state-, and probably singlet oxygen-, mediated phototoxic mechanism. Photoisomerization or singlet state mechanisms can be discounted.

Animals↗

PubMed1985

Characterization of barbiturate-stimulated chloride efflux from rat brain synaptoneurosomes.

Membrane chloride (Cl-) permeability was studied in a novel subcellular brain preparation, the synaptoneurosome. Using a radioactive tracer exchange technique, Cl- transport was determined by measuring 36Cl- efflux from rat cerebral cortical synaptoneurosomes. Barbiturates increased 36Cl- efflux in a dose-dependent manner with the following relative order of potency: 5-(1,3-dimethylbutyl)-5-ethyl barbituric acid ((-)-DMBB) greater than pentobarbital greater than secobarbital greater than (+)-DMBB greater than hexobarbital greater than amobarbital greater than mephobarbital. Phenobarbital and barbital were virtually inactive. A good correlation was observed between the potencies of these barbiturates in stimulating 36Cl- efflux and their anesthetic potencies in mice (r = 0.90, p less than 0.01) and their abilities to enhance [3H] diazepam binding to brain membranes (r = 0.77, p less than 0.05). The effect of pentobarbital in enhancing 36Cl- efflux was reversed by the gamma-aminobutyric acid (GABA) antagonists picrotoxin and bicuculline. Picrotoxin and bicuculline both decreased 36Cl- efflux in the absence of pentobarbital, suggesting the presence of endogenous GABA. Incubation of synaptoneurosomes with 4,4'-di-isothiocyano- or dinitro-2,2'-disulfonic acid stilbene, inhibitors of anion transport, also decreased both basal and pentobarbital-induced 36Cl- efflux. Pentobarbital (500 microM) was most effective in inducing 36Cl- efflux in the cerebellum, hippocampus, and cortex (23.7, 23.6, and 22.5%, respectively), and was less effective in stimulating 36Cl- efflux in the striatum (15.1%) and pons-medulla (6.2%). The relative efficacy of pentobarbital in enhancing 36Cl- efflux among these various brain regions was highly correlated (r = 0.96, p 0.01) with the relative densities of [35S]-t-butylbicyclophosphorothionate-binding sites, a measure of GABA-gated Cl- channel density.(ABSTRACT TRUNCATED AT 250 WORDS)

Amobarbital↗

PubMed2007

Status of lipid peroxidation, glutathione, ascorbic acid, vitamin E and antioxidant enzymes in patients with osteoarthritis.

BACKGROUND: The exact pro-oxidant and antioxidant status in osteoarthritis patients is still not clear. To add a new insight to the question, changes in the erythrocyte lipid peroxidation products (MDA), levels of glutathione (GSH), ascorbic acid and plasma vitamin E (nonenzymatic antioxidant parameters); and activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase in erythrocytes and plasma glutathione - S - transferase (GST) were measured in patients with osteoarthritis. AIM: This work was undertaken to assess oxidative stress and antioxidant status in patients with osteoarthritis. SETTINGS AND DESIGN: The study was conducted in 20 patients and compared to controls. Levels of erythrocyte MDA, GSH, ascorbic acid, plasma vitamin E; and activities of antioxidant enzymes were measured in patients with osteoarthritis. MATERIALS AND METHODS: Erythrocyte GSH was measured by the method of Beutler et al. Ascorbic acid levels were measured by the method of Tietz. Plasma vitamin E levels were measured by the method of Baker et al. MDA was determined as the measure of thio barbituric acid reactive substances (TBARS). SOD activity in the hemolysate was measured by the method of Misra and Fridovich. Activity of catalase was measured by the method of Beers and Sizer. GPX activity was measured as described by Paglia and Valentine in erythrocytes and Plasma GST activity was measured as described by Warholm et al. These parameters were measured in 20 patients and compared to controls. STATISTICAL ANALYSIS: Statistical analysis between group 1 (controls) and group 2 (patients) was performed by the student's t - test using the stat -view package. RESULTS: It was observed that there was a significant increase in erythrocyte MDA levels; SOD, GPX and plasma GST activities; and a significant decrease in erythrocyte GSH, ascorbic acid, plasma vitamin E levels and catalase activity in patients with osteoarthritis when compared to controls. CONCLUSIONS: The results of our study suggest higher oxygen-free radical production, evidenced by increased MDA and decreased GSH, ascorbic acid, vitamin E and catalase activity, support to the oxidative stress in osteoarthritis. The increased activities of antioxidant enzymes may be a compensatory regulation in response to increased oxidative stress.

Adult↗

PubMed1978

Electrophoretic separation of alkaline and acid phosphatase isoenzymes from the pulp of monkey teeth.

Monkey pulps were homogenized in a Triton tris solution. After three centrifugation steps (800, 20000, and 105000 g) the supernatant was applied on acryl amide columns at pH 7.5 in a tris-diethyl barbituric acid buffer. Electrophoresis was performed at a constant current of 2.5 mA per gel column at 18--20 degrees C. Incubations for alkaline phosphatase (E.C. 3.1.3.1) were carried out at pH 8.3 using naphthol-AS-MX-phosphate as substrate and Fast Red Violet LB salt as coupler. Incubations for acid phosphatase (E.C. 3.1.3.2) were undertaken at pH 5.0 using alpha-naphtyl phosphate as substrate and hexazotized pararosanilin as coupling agent. After the incubations for alkaline phosphatase as well as acid phosphatase two bands showing enzyme activity were demonstrated. By means of treatment with heat (56 degrees C) prior to incubation or addition of vanadate or pyrophosphate to the incubation medium it was shown that the main part of the fast moving alkaline phosphatase band was sensitive to these procedures. The alkaline phosphatase of the slow moving band appeared to be resistant to heat or the addition of inhibitors.

Acid Phosphatase↗

PubMed1975

Modification of the surface structure of murine peritoneal macrophages following chemotherapy. A scanning electron microscopic study.

The effects on peritoneal macrophages of some chemotherapeutic agents administered subcutaneously to conventional male AB/Jena mice were studied. beta-[1-ethyl-(5-bis-(beta-chloroethyl)-aminobenzimidazolyl-(2)]-DL-alanine (IMET 2925), beta-[1-phenyl-5-bis-(beta-chloroethyl)-amino-benzimidazolyl-(2)]-DL-alanine (IMET 3164), and gamma-[1-phenyl-5-bis-(beta-chloroethyl)-amino-benzimidazolyl-(2)]-butyric acid (IMET 37/70) evoked a pronounced variation of the cell surface consisting in a shortening, coarsening and reduction in number of the microvili and other projections. Likewise, 1.3-bis(piperidinomethyl)-5-ethyl-5-phenyl-barbituric acid induced a flattening of the surface, but the structures appeared to be increased in number per area. Chlorambucil, 6-mercaptopurine, and 5-fluoro-uracil failed to provoke any obvious change in the threedimensional cell surface structure. These morphological findings are consistent with functional results reported previously.

Animals↗

PubMed1975

Permeability of selected drugs and chemicals across the blood-testis barrier of the rat.

Physiological studies by Setchell and others have described the existence of a blood-testis barrier (BTB) surrounding the seminiferous tubules of the mammalian testis. These studies were initiated to better define the role of the BTB with regard to the penetration of exogenous chemicals to male germ cells. The rete testis was cannulated in rats and fluid was collected. Test chemicals or drugs were usually administered by continuous i.v. infusion. Permeability of nonelectrolytes of various molecular sizes, acidic compounds with varying partition coefficients and pKalpha values, such as salicylic acid, barbiturates, and sulfonamides, across the BTB were studied. Permeability of nonelectrolytes was demonstrated to be dependent upon their molecular size, suggesting bulk flow through water-filled pores. On the other hand, permeability of acidic drugs with varying pKalpha values depended upon their partition coefficients. Transport of these chemicals from blood to seminferous tubules closely resembled their transport from blood to cerebrospinal fluid. It appears that the BTB is a complex multicellular system composed of membranes surrounding the semiferous tubules and the several layers of spermatogenic cells organized within the tubules, which restrict the permeability to the male germ cells of many foreign compounds. This must be borne in mind when extra-polating data from in vitro mutagenic test systems to man.

Animals↗

PubMed1983

Actions of pentobarbitone and derivatives with modified 5-butyl substituents on GABA and diazepam binding to rat brain synaptosomal membranes.

The effects of a variety of factors known to influence the enhancement of GABA binding by diazepam, were studied upon pentobarbitone stimulation of GABA binding to washed synaptosomal membranes prepared from whole rat brains. The differential kinetics of, and effects of temperature, chloride ions, a benzodiazepine receptor antagonist (Ro15-1788) and picrotoxinin upon pentobarbitone and diazepam enhancement of GABA binding, suggest that these drugs exert their actions upon GABA binding at different loci. The degree of enhancement of diazepam binding and of high affinity GABA binding in chloride-containing media at 25 degrees C by members of a series of twelve side chain methyl substituted and/or unsaturated derivatives of 5-butyl-5-ethyl-barbituric acid (pentobarbitone analogs) correlated significantly. For the sedative members of the series, enhancement of high affinity GABA binding correlated with their anaesthetic but not their anticonvulsant activities. It appears likely that the anaesthetic and anticonvulsant activities of barbiturates arise from different molecular actions.

Animals↗