[Studies on the structure-activity relationship of allyl substituted oxopyrimidines searching for the novel antagonist or agonist of barbiturates to the sleep mechanism based on the uridine receptor theory--barbituric acid to uridine (part I)].

Thirty-six allyl substituted oxopyrimidine analogues such as barbituric acid (BA), barbiturates, uracil, thymine, and related derivatives including 13 new compounds were synthesized and their pharmacologic effects ([hypnotic activity, anticonvulsant activity against pentylentetrazol (PTZ)-induced seizures, and LD(50)]) and interactions with the barbiturates were evaluated in mice and rats. The results are briefly and parially summarized as follows. BA prolonged pentobarbital (PB)-induced sleep and had some central depressant effects. N,5,5-triallyl-BA exhibited some hypnotic and anticonvulsant activities, although the other 5,N-allyl-compounds did not show any activity except for allobarbital (AlloB). N-allyl-BA, 5-allyl-BA, N(1),N(3),5-triallyl-BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA also prolonged PB-induced sleep. Interestingly, N,5,5-triallyl-BA was the most potent in the interaction with AlloB, phenobarbital (PheB), amobarbital (AB), PB, and thiopental (TP) but not barbital (B). N(1),N(3),5,5-tetraallyl-BA prolonged AlloB-, PB-, and AB-induced sleep but not B-, PheB-, and TP-induced sleep. N(1),N(3),5-triallyl-B prolonged only PB- and TP-induced sleep. 5,5-diallyl-BA prolonged PheB- and TP-induced sleep. N,5-diallyl-BA prolonged only TP-induced sleep. In contrast, BA and N(1),N(3),5-triallyl-AB tended to antagonize AlloB, AB, and B. N(1),N(3),5,5-tetraallyl-BA also slightly antagonized B, PheB, and TP. 5,5-diallyl-BA antagonized only AB. The prolonging effects of BA, N,5,5-triallyl-BA, and N(1),N(3),5,5-tetraallyl-BA on PB-induced sleep were dose dependent. These results indicate that the position and number of allyl groups substituted on the structure of BA play an important role in their depressant activities. This review deals with the structure-activity relationship of allyl-substituted oxopyrimidines as part of our search for antagonists and agonists of barbiturates as well as their mechanisms of action.

Prodrugs to enhance central nervous system effects of the TRH-like peptide pGlu-Glu-Pro-NH2.

Potential prodrugs for the TRH-like tripeptide pGlu-Glu-Pro-NH(2) were synthesized either by esterifying the Glu side-chain of the parent peptide in solution with alcohols in the presence of resin-bound dicyclohexylcarbodiimide or by solid-phase peptide chemistry. Affinities of these ester prodrugs to lipid membranes as predictors of the transport across the blood-brain barrier were compared by immobilized artificial membrane chromatography, and prodrug activation was tested in the brain tissue of experimental animals. Esters of pGlu-Glu-Pro-NH(2) with long-chain primary alcohols emerged as potentially useful prodrugs to improve the central nervous system activity of pGlu-Glu-Pro-NH(2) upon systemic administration, as revealed by the enhancement of analeptic activity in mice.

Mutation of the GABAA receptor M1 transmembrane proline increases GABA affinity and reduces barbiturate enhancement.

All GABA(A) receptor (GABAR) subunits include an invariant proline in a consensus motif in the first transmembrane segment (M1). In receptors containing bovine alpha1, beta1 and gamma2 subunits, we analyzed the effect of mutating this M1 proline to alanine in the alpha1 or beta1 subunit using 3 different expression systems. The beta1 subunit mutant, beta1(P228A), reduced the EC(50) for GABA about 10-fold in whole cell recordings in HEK293 cells and L929 fibroblasts. The corresponding alpha1 subunit mutant (alpha1(P233A)) also reduced the GABA EC(50) when expressed in Xenopus oocytes; alpha1(P233A)beta1gamma2S receptors failed to assemble in HEK293 cells. Binding of [(3)H]flumazenil and [(3)H]muscimol to transfected HEK293 cell membranes showed similar levels of receptor expression with GABARs containing beta1 or beta1(P228A) subunits and no change in the affinity for [(3)H]flumazenil; however, the affinity for [(3)H]muscimol was increased 6-fold in GABARs containing beta1(P228A) subunits. In L929 cells, presence of the beta1(P228A) subunit reduced enhancement by barbiturates without affecting enhancement by diazepam or alfaxalone. Single channel recordings from alpha1beta1gamma2S and alpha1beta1(P228A)gamma2L GABARs showed similar channel kinetics, but beta-mutant containing receptors opened at lower GABA concentrations. We conclude that the beta1 subunit M1 segment proline affects the linkage between GABA binding and channel gating and is critical for barbiturate enhancement. Mutation of the M1 proline in the alpha1 subunit also inhibited receptor assembly.

Antipsychotic profile of alstonine: ethnopharmacology of a traditional Nigerian botanical remedy

Although recently developed drugs have brought significant improvement, the treatment of psychotic disorders still presents serious drawbacks. Since inherent complexity and lack of satisfactory understanding of the underlying pathophysiology impose limits for rational drug design, resourceful approaches in the search for antipsychotics are pertinent. This paper reports pharmacological properties of alstonine, a heteroyohimbine type alkaloid, Which exbitited an antipsychotic-like profile, inhibiting amphetamine-induced lethaly, apomorphine-induced steotypy and potentiating barbiturate-induced slleping time. Atypical features of alstonine were the prevention of haloperidol-induced catalepsy and lack of direct interaction with D1, D2 and 5-HT2A receptors, classically linked to antipsychotic mechanism of action.

[An analysis of the mechanism of the resistance to barbiturate action by using exogenous RNA]. / Analiz mekhanizma rezistentnosti k deistviiu barbituratov s pomoshch'iu ékzogennykh RNK.

For the first time the experimental method of exogenous RNA has been used to evaluate the role of protein synthesis in different organs for the development of resistance to the soporific effect of barbiturates. Liver cytosolic RNA of phenobarbital-treated donors was found to reproduce completely the effect of phenobarbital-induced resistance to barbiturates in recipient rats: the reduction of hexenal-induced sleep and the increase of cytochrome P450 content in hepatic microsomes. Brain and renal RNAs had no influence on recipients. These data demonstrate the decisive role of microsomal R450-contained enzymes synthesis in the mechanism of the development of barbiturate resistance. It is concluded that exogenous RNA technique is of value for the organ-specific analysis of various complicated biological phenomena resulted from the activation of protein synthesis. The mechanism of exogenous RNA action and the possibility of cellular interactions by means of RNA molecules are also discussed.

Efecto de una beta lactama de 1.5 benzodiazepina sobre el sueño / Effect of a beta lactame of 1.5 benzodiacepine upon sleep

Existen numerosas substancias, de estructura química diversa que han sido utilizadas como inductoras de sueño. Sin embargo, debido a que producen efectos colaterales indeseables, constantemente son substituidas por fármacos de reciente creación. Este trabajo se llevó a cabo con el propósito de analizar el efecto sobre el sueño de una beta lactama de 1.5 benzodiazepina, administrada intraperitonealmente (0.9 mg/kg) a ratas wistar. Los resultados indican que esta substancia incrementa de manera significativa, tanto al sueño lento como al paradójico a expensas de la vigilia. La lactancia de la primera fase de sueño paradójico, se prolonga significativamente. Se concluye que esta substancia facilita la presencia de sueño, manifestándose su acción durante un período relativamente largo

[Stimulation of respiration with Piladox in experimental and clinical conditions during administration of drugs for general anesthesia]. / Stimuliatsiia dykhaniia Piladoksom v éksperimente i klinike v usloviiakh primeneniia sredstv dlia obshchei anestezii.

Experimental and clinical studies of the agent Piladox (RGH 2202) were conducted. Experiments on animals (rats, rabbits, mice) demonstrated that Piladox possesses the property of restoring respiration inhibited by narcotic analgesics and some general anesthetics as well as the respiratory-de-priming effect of acute blood loss and is a more effective stimulator of the respiratory center than cordiamine (nikethamide) or corasol. Clinical study of Piladox in 75 patients showed that intravenous infusion of 1 mg/kg of the agent in the awakening period produced a stimulating effect on respiration through increase of its frequency and increase of the respiratory volume. The minute respiratory volume in this case was even greater than the initial values, whereas the CO2 content in the blood and expired air reached the initial level. The hemodynamic values in this period remained generally stable. Piladox does not change the antinociceptive effect of the narcotic analgesics and analgesia in the immediate postoperative period when combined general anesthesia is applied.

[Pharmacological effects of the novel dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride (I-893) on the central nervous system].

The effects of 1-[2-[bis (4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl) piperazine dihydrochloride (I-893) on the central nervous system were behaviorally and electroencephalographically investigated. Intraperitoneally injected I-893 (5-10 mg/kg) dose-dependently increased spontaneous motor activity in mice, but repeated injections did not affect the increase in the locomotor activity. In reserpinized mice, spontaneous motor activity was not increased by oral I-893. In alpha-MPT-treated mice, the motor activity was lower than that in vehicle-treated animals with intermediate doses (10-40 mg/kg, p.o.) of I-893, but there was no difference between the two groups with high doses. In rats with unilaterally 6-OHDA-induced lesion of the nigrostriatal pathway, I-893 induced circling behavior toward the lesioned side. Haloperidol-induced catalepsy in rats was reduced by I-893. Tremorine-induced tremor in mice was inhibited by I-893. The effect was not altered in the mice treated with I-893 for 10 days. Oral I-893 induced stereotypy in rats, but it did not affect methamphetamine-induced stereotypy. Hypnosis induced by barbiturates was antagonized by I-893. In rats treated with I-893 for 6 days, pentobarbital-induced sleep was not different from that in vehicle-treated animals on the day after the final treatment. Intravenous I-893 altered EEGs in the cerebral cortex and amygdala nucleus to low voltage and fast waves and altered hippocampal EEG to theta waves in immobilized rabbits. These results suggest that I-893 inhibits re-uptake of dopamine released by exocytosis and indirectly has dopaminergic effects.

[Effector modeling of the action of ligands of GABA-receptor complex. Functional interaction of the hypothetic alcohol receptor with other subunits of the complex]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa. Funktsional'noe vzaimodeistvie gipoteticheskogo retseptora spirtov s drugimi sub"edinitsami kompleksa.

The types of the interaction of the pharmacological effects of ethanol and barbiturate antagonists--picrotoxin, bemegride and corasol--were determined. The effect of ethanol was determined as competitive--for the convulsant effects of bicuculline, and non-competitive--for the effects of thiosemicarbazide. The indices of the anticonvulsant effects of n-aliphatic alcohols were compared. It is suggested that n-aliphatic alcohols alter the functional status of the supramolecular GABA-receptor channel ensemble. The pharmacological properties and the elements of the structural similarity of picrotoxin and n-propanol (the presumptive ligand of the GABA-receptor channel ensemble) are discussed.

Aminophylline reduces the depth and duration of sedation with barbiturates.

Aminophylline, an inhibitor of cyclic nucleotide phosphodiesterase, has for many years been used to relieve bronchospasm. Recent reports have shown that aminophylline antagonizes morphine and diazepam sedation. To see if aminophylline acts similarly on barbiturate sedation, we examined 24 women undergoing short general anaesthesia with thiopental (7 mg x kg-1), using a double-blind study design. Evaluated by continuous auditory reaction time measurements, aminophylline (5.6 mg x kg-1) reduces the depth and duration of sedation with thiopental. This suggests that aminophylline could be used to diminish an unwanted effect of barbiturate sedation.

N,N'-diallylpentobarbital: antagonism of barbital in mice and rats.

N,N'-Diallylpentobarbital (DAPB) antagonized barbital (B)-induced sleep in mice and rats. DAPB [80 mg/kg, intraperitoneal (i.p.)] reduced the barbital (350 mg/kg, i.p.)-induced sleeping time to 40% of the control in mice. Twenty, 40 and 80 mg/kg, i.p. of DAPB reduced barbital-induced sleeping time when administered 60 min prior to injection of barbital. DAPB (80 mg/kg, i.p.) also shortened barbital (250 mg/kg, i.p.)-induced sleeping time to about 70% of the control in rats. The result indicates that DAPB is an antagonist against hypnotic activity of barbital.

Synthesis of thyrotropin-releasing hormone analogues. 2. Tripeptides structurally greatly differing from TRH with high central nervous system activity.

A new series of thyrotropin-releasing hormone (TRH) analogues, obtained by further modifications of our most potent central nervous system (CNS) stimulating neutral tripeptides at both termini, were synthesized by the pentafluorophenyl ester method and tested for CNS and thyrotropin (TSH) releasing activity. Replacement of pyroglutamic acid by pyro-2-aminoadipic acid, 2-oxoimidazolidine-4-carboxylic acid or gamma-butyrolactone-gamma-carboxylic acid and that of proline by pipecolic acid, thiazolidine-4-carboxylic acid, or homoproline in [Leu2]- and [Nva2]TRH led to tripeptides structurally widely different from TRH. In spite of this fact, 7 of the 17 analogues (1, 2, 8-10, 16, and 17) have stronger anticataleptic effect than TRH, with negligible or no hormonal potency. The highest CNS activity was achieved when pyroglutamic acid was replaced by pyro-2-aminoadipic acid at the N-terminus [pAad-Leu-Pro-NH2, 1 (RGH 2202), and pAad-Nva-Pro-NH2,2]. A novel synthesis of L-2-aminoadipic acid suitable for large-scale preparation is also described.

Continuously infused 2-amino-7-phosphonoheptanoic acid antagonizes N-methyl-D-aspartate-induced elevations of cyclic GMP in vivo in multiple brain areas and chemically-induced seizure activity.

The effects of the chronic intracerebroventricular (i.c.v.) infusion of the potent dicarboxylic amino acid antagonist, 2-amino-7-phosphonoheptanoic acid (APH), were examined in female rats as a prelude to the use of this compound in exploring the role of dicarboxylic amino acids in barbiturate dependence and withdrawal. Doses of APH ranging from 2.7 to 54 micrograms/day were examined for signs of toxicity. Weight loss, decreased water intake and locomotor impairment were found only with the largest dose. No significant changes in consumption of food or body temperature were observed with any dose. The chronic administration of the drug (27 micrograms/day) blocked the elevation of the content of cyclic guanosine monophosphate induced by N-methyl-D-aspartate (NMDA) in all regions of the brain examined. The chronically-administered drug also blocked wild running behavior induced by the intracerebroventricular administration of two different drugs n-methyl-D-aspartic acid and cyclohexylbarbiturate acid. However, APH was ineffective in suppressing convulsions induced by the ED50 dose of pentylenetetrazol given subcutaneously.

RO 15-1788 selectively reverses antagonism of pentylenetetrazol-induced discriminative stimuli by benzodiazepines but not by barbiturates.

The specificity of ethyl 8-fluro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a) (1,4) benzodiazepine-3-carboxylate (RO 15-1788) in reversing the effectiveness of diazepam and des-methylclobazam, but not of pentobarbital, in antagonizing discriminative stimuli produced by pentylenetetrazol is described. Male hooded rats were trained to discriminate pentylenetetrazol-induced interoceptive discriminative-stimuli (IDS) in a two-lever choice paradigm on an FR10 schedule of food reinforcement. These IDS pharmacologically model verbal report of anxiogenic activity in humans. Diazepam (1,4 benzodiazepine), des-methylclobazam (1,5 benzo-diazepine), and pentobarbital antagonized pentylenetetrazol-IDS. RO 15-1788 neither generalized to nor antagonized pentylenetetrazol-IDS. It also did not cause convulsions in pentylenetetrazol sensitized rats at doses up to 40 mg/kg. It did, however, antagonize the action of diazepam (10 mg/kg) as well as that of des-methylclobazam (160 mg/kg) but not that of pentobarbital. These data suggest that RO 15-1788 is not an anxiomimetic, anxiolytic or a convulsant drug, but it is a specific and effective antagonist of anxiolytic action of benzodiazepines.

A calcium reversible action of barbiturates on the leech Retzius cell.

The Na salts of phenobarbital, barbital, pentobarbital, secobarbital, methohexital and thiopental in concentrations of 1 to 5 mM all caused prolonged action potentials in leech Retzius cells. The prolongation was favored by low Ca and was reversible by elevation of Ca. Barbiturate-prolonged action potentials were not affected by 50 micronm tetrodotoxin or replacement of Cl by propionate, but they were dependent on external Na. Their amplitudes were increased by steady hyperpolarization and input resistance was reduced during them. They were of shorter duration when elicited at a rapid rate. They were sometimes shortened by intracellular iontophoresis of Ca and by use of the ionophore X537A, but technical factors complicated the interpretation of both kinds of experiments. The results are consistent with the hypothesis that the barbiturates used blocked a voltage-dependent inward Ca current which activates a K conductance necessary for normal repolarization.

[An experimental study of the psychostimulant action of amantadine]. / Etude expérimentale de l'action psycho-stimulante de l'amantadine

According to previous experimental and clinical data, we have tested the hypothetic psycho-stimulating activity of amantadine on experimental sensitized models. We obtained a strong action on the spontaneous sleep of rats at a dose of 10 mg/kg and a less striking action in diminishing the effects of barbitol on the righting reflex of mice and in reducing the narcosis of rats induced by mebubarbital. This action does not seem to be due to a release of catecholamine because the lesions produced by electrocoagulation in the ascending aminergic pathways or pretreatment by alpha-methylparatyrosine (AMPT) do not block it. It is suggested that there may be a non-aminergic receptor of amantadine which is different from the amphetamine receptor.