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PubMedDate not supplied

[Pharmacological characteristics of the tranquilizing action of hydiphen].

Hydiphen--hydrazide of diphenylphosphinylacetic acid--is a new Soviet tranquilizer having an original spectrum of psychotropic activity. It depresses an aroused emotional state of fear-anxiety, decreases the state of conflict in group interaction. It produces neither myorelaxation nor increase in positive emotions. The drug is not toxic. It possesses the central N-cholinolytic, antiadrenergic and antiserotonin effects.

Animals↗
PubMed1984

Post-translational activation introduces a free radical into pyruvate formate-lyase.

Pyruvate formate-lyase (formate acetyltransferase; EC 2.3.1.54) of Escherichia coli cells is post-translationally interconverted between inactive and active forms. Conversion of the inactive to the active form is catalyzed by an Fe2+-dependent activating enzyme and requires adenosylmethionine and dihydroflavodoxin. This process is shown here to introduce a paramagnetic moiety into the structure of pyruvate formate-lyase. It displays an EPR signal at g = 2 with a doublet splitting of 1.5 mT and could comprise an organic free radical located on an amino acid residue of the polypeptide chain. Hypophosphite was discovered as a specific reagent that destroys both the enzyme radical and the enzyme activity; it becomes covalently bound to the protein. The enzymatic generation of the radical, which is linked to adenosylmethionine cleavage into 5'-deoxyadenosine and methionine, possibly occurs through an Fe-adenosyl complex. These results suggest a radical mechanism for the catalytic cycle of pyruvate formate-lyase.

Acetyltransferases↗
PubMed1996

Adenosine by activating A1 receptors prevents GABAA-mediated actions during hypoxia in the rat hippocampus.

The relative contribution of adenosine and gamma-aminobutyric acid (GABA) for the hypoxia-induced depression of field excitatory postsynaptic potentials in the CA1 area of rat hippocampal slices, was investigated. It is concluded that both adenosine and GABA, by activating A1 and GABAA receptors, could be responsible for the inhibition of synaptic transmission during hypoxia, but the action of endogenous GABA becomes evident only when the adenosine A1 receptor action is precluded.

Adenosine↗
PubMed2004

The spinal GABAergic system is a strong modulator of burst frequency in the lamprey locomotor network.

The spinal network coordinating locomotion is comprised of a core of glutamate and glycine interneurons. This network is modulated by several transmitter systems including spinal GABA interneurons. The purpose of this study is to explore the contribution of GABAergic neurons to the regulation of locomotor burst frequency in the lamprey model. Using gabazine, a competitive GABAA antagonist more specific than bicuculline, the goal was to provide a detailed analysis of the influence of an endogenous activation of GABAA receptors on fictive locomotion, as well as their possible interaction with GABAB and involvement of GABAC receptors. During N-methyl-D-aspartate (NMDA)-induced fictive locomotion (ventral root recordings in the isolated spinal cord), gabazine (0.1-100 microM) significantly increased the burst rate up to twofold, without changes in regularity or "burst quality." Gabazine had a proportionately greater effect at higher initial burst rates. Picrotoxin (1-7.5 microM), a less selective GABAA antagonist, also produced a pronounced increase in frequency, but at higher concentrations, the rhythm deteriorated, likely due to the unspecific effects on glycine receptors. The selective GABAB antagonist CGP55845 also increased the frequency, and this effect was markedly enhanced when combined with the GABAA antagonist gabazine. The GABAC antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) had no effect on locomotor bursting. Thus the spinal GABA system does play a prominent role in burst frequency regulation in that it reduces the burst frequency by < or =50%, presumably due to presynaptic and soma-dendritic effects documented previously. It is not required for burst generation, but acts as a powerful modulator.

Algorithms↗
PubMed2006

Combined use of selective inhibitors and fluorogenic substrates to study the specificity of somatic wild-type angiotensin-converting enzyme.

Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. Studies on the selectivity of these ACE domains towards either substrates or inhibitors have mostly relied on the use of mutants or isolated domains of ACE. To determine directly the selectivity properties of each ACE domain, working with wild-type enzyme, we developed an approach based on the combined use of N-domain-selective and C-domain-selective ACE inhibitors and fluorogenic substrates. With this approach, marked differences in substrate selectivity were revealed between rat, mouse and human somatic ACE. In particular, the fluorogenic substrate Mca-Ala-Ser-Asp-Lys-DpaOH was shown to be a strict N-domain-selective substrate of mouse ACE, whereas with rat ACE it displayed marked C-domain selectivity. Similar differences in selectivity between these ACE species were also observed with a new fluorogenic substrate of ACE, Mca-Arg-Pro-Pro-Gly-Phe-Ser-Pro-DpaOH. In support of these results, changes in amino-acid composition in the binding site of these three ACE species were pinpointed. Together these data demonstrate that the substrate selectivity of the N-domain and C-domain depends on the ACE species. These results raise concerns about the interpretation of functional studies performed in animals using N-domain and C-domain substrate selectivity data derived only from human ACE.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Discovery of novel phosphonic acid derivatives as new chemical leads for inhibitors of TNF-alpha production.

2-(Acylamino)benzylphosphonic acid 6 derived from an artificial substrate of sphingomyelinase was found to show inhibitory activity of TNF-alpha production. Structural optimization was started with the chemical modification of 6. The discovery of another chemical leads 7, 8, 10 and 16 for the development of structurally new inhibitors of TNF-alpha production is reported.

Animals↗
PubMed2000

GABArho 1/GABAAalpha 1 receptor chimeras to study receptor desensitization.

gamma-Aminobutyrate type C (GABA(C)) receptors are ligand-gated ion channels that are expressed preponderantly in the vertebrate retina and are characterized, among other things, by a very low rate of desensitization and resistance to the specific GABA(A) antagonist bicuculline. To examine which structural elements determine the nondesensitizing character of the human homomeric rho1 receptor, we used a combination of gene chimeras and electrophysiology of receptors expressed in Xenopus oocytes. Two chimeric genes were constructed, made up of portions of the rho1-subunit and of the alpha1-subunit of the GABA(A) receptor. When expressed in Xenopus oocytes, one chimeric gene (rho1/alpha1) formed functional homooligomeric receptors that were fully resistant to bicuculline and were blocked by the specific GABA(C) antagonist (1,2,5, 6-tetrahydropyridine-4-yl)methylphosphinic acid and by zinc. Moreover, these chimeric receptors had a fast-desensitizing component, even faster than that of heterooligomeric GABA(A) receptors, in striking contrast to the almost nil desensitization of wild-type rho1 (wt rho1) receptors. To see whether the fast-desensitizing characteristic of the chimera was determined by the amino acids forming the ion channels, we replaced the second transmembrane segment (TM2) of rho1 by that of the alpha1-subunit of GABA(A). Although the alpha1-subunit forms fast-desensitizing receptors when coexpressed with other GABA(A) subunits, the sole transfer of the alpha1TM2 segment to rho1 was not sufficient to form desensitizing receptors. All this suggests that the slow-desensitizing trait of rho1 receptors is determined by a combination of several interacting domains along the molecule.

Animals↗
PubMed2000

Light-evoked responses of bipolar cells in a mammalian retina.

We recorded light-evoked responses from rod and cone bipolar cells using patch-clamp techniques in a slice preparation of the rat retina. Rod bipolar cells responded to light with a sustained depolarization (ON response) followed at light offset by a slight hyperpolarization. ON and OFF cone bipolar cells were encountered, both with diverse temporal properties. The responses of rod bipolar cells were composed primarily of two components, a nonspecific cation current and a chloride current. The chloride current was reduced greatly in axotomized cells and could be suppressed by coapplication of the GABA(A) antagonist bicuculline and the GABA(C) antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid. This suggests that it largely reflects feedback from GABAergic amacrine cells. The response latency of intact rod bipolar cells was shorter than that of the axotomized cells, and the sensitivity curve covered more than twice the dynamic range. Application of the GABA receptor antagonists partially mimicked the effects of axotomy. These findings suggest that functional properties of the axon terminal system-notably synaptic feedback from amacrine cells-play an important role in defining the response properties of mammalian bipolar cells.

Animals↗
PubMed2004

Voltammetric and drift spectroscopy investigation in dithiophosphinate-chalcopyrite system.

The mechanism of dithiophosphinate (DTPI) adsorption on chalcopyrite was investigated by diffuse reflectance Fourier transformation (DRIFT) spectroscopy and by cyclic voltammetry (CV) at various pHs. CV experiments showed that the redox reactions occurred at a certain degree of irreversibility on the chalcopyrite surface in the absence of a collector due to preferential dissolution of iron ions in slightly acid solution and irreversible surface coverage by iron oxyhydroxides in neutral and alkaline solutions. In the presence of DTPI, CV experiments failed to identify the type of the adsorbed DTPI species and electrochemical processes occurring on chalcopyrite due to formation of an electrochemically passive surface layer preventing electron transfer. However, DRIFT spectroscopy tests showed this passive layer to be mainly CuDTPI + (DTPI)2. Both CV and DRIFT spectroscopy established that the activity of collector species decreased with increasing pH due to formation of stable hydrophilic metal oxyhydroxides on the chalcopyrite surface.

Adsorption↗
PubMed1980

[Effect of gidifen on behavior and hemodynamic signs of an emotionally stressful reaction].

Gidifen (diphenylphosphinylacetic acid hydrazide) is an original Soviet tranquilizer. In doses of 120--150 mg/kg it restores central baroreflex regulation of the arterial pressure supressed during acute emotional-stress reaction in cats (confrontation with a dog). The drug has an antihypertensive action and reduces tachycardia caused by the emotional stress. It has a selective antiphobic and antiaggressive action and does not produce ataxia. Quantitative evaluation of behavior was performed during group interaction of animals according to the five-point system.

Administration, Oral↗
PubMed1999

The next generation of MMP inhibitors. Design and synthesis.

Since their inception during the eighties, MMP inhibitors (MMPIs) have gone through several cycles of metamorphosis. The design of early MMPIs was based on the cleavage site of peptide substrates. The second generation contained a substituted succinate scaffold (e.g., marimastat) coupled to a modified amino acid residue. The lower molecular weight analogs with multiple substitution possibilities produced a series of MMP inhibitors with varying degrees of selectivity for various MMPs. The introduction of sulfonamides in the midnineties added a new dimension to this field. The simplicity of synthesis coupled with high potency (e.g., CGS-27023A, AG-3340) produced a number of clinical candidates. This review highlights some of the key features that contributed to the discovery of this novel series of MMP inhibitors.

Caprolactam↗
PubMed1999

Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists.

Transient lower esophageal sphincter (LES) relaxation is the major mechanism of gastroesophageal reflux. This study uses an established ferret model to evaluate GABA(B) receptor agonists' ability to reduce triggering of transient LES relaxations. One hundred sixty manometric/pH studies were performed on 18 conscious ferrets. In untreated animals, intragastric infusion of 25 ml glucose (pH 3.5) led to 2.0 +/- 0.6 reflux episodes over the first 30 min. Twenty-nine of forty-seven reflux episodes occurred during transient LES relaxation, and 18 occurred after downward drifts (<1 mmHg/s) in basal LES pressure. The GABA(B) receptor agonists baclofen (7 micromol/kg ip), CGP-44532, and SKF-97541 (both ED(50) <0.3 micromol/kg) reduced reflux episodes and transient LES relaxations. The putative peripherally selective GABA(B) receptor agonist 3-aminopropylphosphinic acid (80-240 micromol/kg) was ineffective, as was the GABA(A) receptor agonist muscimol (5 micromol/kg). Baclofen's inhibition of transient LES relaxations and reflux was unaffected by low-affinity GABA(B) receptor antagonists CGP-35348 and CGP-36742 at 100 micromol/kg but was reversed by higher-affinity CGP-54626 and CGP-62349 (0.7 micromol/kg) or by CGP-36742 at 200 micromol/kg. Therefore, GABA(B) receptor inhibition of reflux shows complex pharmacology. Our and other data indicate the therapeutic potential for these drugs.

Animals↗
PubMed1999

alpha-Functionalized phosphonylphosphinates: synthesis and evaluation as transcarbamoylase inhibitors.

Diverse alpha-methyl-substituted phosphonylphosphinates (P-C-P-C-X) are accessible from a protected, pentafluorophenylsulfonated phosphonylphosphinate via nucleophilic displacement. The utility of this route is demonstrated with several nitrogen nucleophiles. The resulting amine and amino acid phosphonylphosphinate derivatives were evaluated as inhibitors of Streptococcus faecalis ornithine transcarbamoylase (OTC). Compared with the structurally related phosphonoacetyl-L-ornithine (L-PALO), a known inhibitor of OTCs from various sources, the phosphonylphosphinates are surprisingly poor inhibitors, binding several orders of magnitude less tightly to the enzyme. These results suggest that the tetrahedral intermediate formed in the normal transcarbamoylase reaction is poorly mimicked by a tetrahedral and anionic phosphonate, either because of directly unfavorable interactions with a hydrogen-bond acceptor within the active site or because transition-state analogues are unable to induce the protein conformation changes that normally accompany reaction.

Colorimetry↗
PubMed2006

Three in one: TSA, TSA', and SA units in one crystal structure of a yttrium(III) complex with a monophosphinated H4dota analogue.

Compound [Y(Hdo3aP(ABn))(H2O)][Y(Hdo3aP(ABn))].6H2O.iPrOH, where H4do3aP(ABn) is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic-10-methyl(4-aminobenzylphosphinic) acid, a monophosphinate analogue of H4dota, was prepared in the solid state and studied using X-ray crystallography. In contrast to all single-crystal structures of complexes of H4dota-like ligands published before, three distinct units were found in one cell: two species adopting a twisted-square-antiprismatic configuration with (TSA) and without (TSA') a coordinated water molecule and one isomer with a square-antiprismatic configuration (SA). In addition, this is the first complex with the H4dota-like ligand for which the structures of three possible species were determined in the solid state.

Aza Compounds↗
PubMed2001

Study of a GABAC receptor antagonist on sleep-waking behavior in rats.

RATIONALE: gamma-Aminobutyric acid (GABA) is the main inhibitory transmitter of the brain. The involvement of GABAA and GABAB receptors in sleep-waking processes is well established. OBJECTIVES: This research studied the influence of GABAC receptors. METHODS: The rats were randomly infused in the fourth ventricle with vehicle and 25, 50, and 100 micrograms (1,2,5,6,-tetrahydropyridine)-methylphosphinic acid (TPMPA), a specific antagonist of GABAC receptors. RESULTS: Principally at 50 micrograms, the molecule induced an increase of waking from 44.7% to 61.7% (P < 0.003), which was the consequence of enhancement of both active and quiet wakefulness. Total slow wave sleep was decreased, particularly the slow-wave stage from 39% to 27.7% (P < 0.02). Paradoxical sleep was also decreased from 14.5% to 9.1% (P < 0.01). CONCLUSIONS: GABAC receptors are also involved in sleep-waking regulation. Since the sensitivity of GABAC receptors to GABA is much higher than that of GABAA and GABAB receptors, GABAC receptor modulators could be potential medications acting at low doses with fewer side effects.

Animals↗
PubMed2001

Attenuation of morphine withdrawal signs by the GABA(B) receptor agonist baclofen.

The present study examined the effect of the gamma-aminobutyric acidB (GABA(B)) receptor agonist, baclofen on naloxone-induced withdrawal signs in morphine-dependent rats and modification by the antagonist, 3-aminopropyl-cyclohexylmethylphosphinic acid (CGP 46381). Morphine was administered via mini-osmotic pumps for 7 days to induce physical dependence. Baclofen (20 mg kg(-1)) decreased stereotyped head movements, chewing, chatter, ptosis and body weight loss, induced by naloxone (10 mg kg(-1)) in morphine-dependent rats. CGP 46381 (20 mg kg(-1)) reversed the effects exerted by baclofen on stereotyped head movements, ptosis, and weight loss and partially reversed the effect of baclofen on chewing. It can be concluded that baclofen has some potential in the treatment of opioid withdrawal and that GABA(B) receptors may be implicated in such a withdrawal.

Animals↗
PubMed2005

Enantiospecificity of glutamate carboxypeptidase II inhibition.

Two representative glutamate carboxypeptidase II (GCP II) inhibitors, 2-(hydroxypentafluorophenylmethyl-phosphinoylmethyl)pentanedioic acid 2 and 2-(3-mercaptopropyl)pentanedioic acid 3, were synthesized in high optical purities (>97%ee). The two enantiomers of 2 were prepared from previously reported chiral intermediates, (R)- and (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl esters 8. The synthesis of (R)- and (S)-3 involves the hydrolysis of (R)- and (S)-3-(2-oxo-tetrahydro-thiopyran-3-yl)propionic acids, (R)- and (S)-11, the corresponding optically pure thiolactones delivered by chiral chromatographic separation of the racemic 11. GCP II inhibitory assay revealed that (S)-2 is 40-fold more potent than (R)-2. In contrast, both enantiomers of 3 inhibited GCP II with nearly equal potency. The efficacy observed in subsequent animal studies with these enantiomers correlated well with the inhibitory potency in a GCP II assay.

Analgesics↗
PubMed2001

Multireceptor GABAergic regulation of synaptic communication in amphibian retina.

The synaptic output of retinal bipolar cells was monitored by recording light-evoked EPSCs in ganglion cells. Application of (RS)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl (ATPA), a selective agonist at kainate receptors, depolarized amacrine cells and reduced the light-evoked excitatory current (L-EPSC) in ganglion cells. ATPA had only a slight effect on the light responses of bipolar cells. Therefore, ATPA suppresses bipolar cell synaptic output to ganglion cells. ATPA reduced the transient L-EPSC, but had comparatively little effect on sustained L-EPSC, of ganglion cells. The transient ON L-EPSC was more suppressed than the transient OFF L-EPSC. Thus, ATPA preferentially suppressed transient output from bipolar cells.GABA receptor antagonists blocked the effect of ATPA. This indicates that ATPA stimulated an endogenous inhibitory feedback pathway that suppressed bipolar cell output.CGP55845 and CGP35348 reduced the ATPA-induced suppression of L-EPSCs in ganglion cells, signifying that part of the feedback pathway is mediated by metabotropic GABA receptors.(1,2,5,6-Tetrahydropyridine-4-yl)-methylphosphinic acid (TPMPA) and picrotoxin, GABAC receptor antagonists, reduced the ATPA effect. Picrotoxin was more effective than ATPA. However, picrotoxin blocked only a part of this GABAC effect, while imidazole-4-acetic acid (I4AA) blocked another segment of the effect. This indicates that two pharmacologically distinct GABAC receptors mediate feedback to bipolar cells. SR95531 produced a very small suppression of the ATPA effect. Thus, GABAA receptors provide a negligible component to this feedback pathway. The experiments indicate that endogenous GABAergic feedback to bipolar cells suppresses their output, and that this feedback is mediated by at least three types of GABA receptor, both metabotropic and ionotropic.In conjunction with previous studies, the results indicate that feedback inhibition is the predominant factor regulating transient signalling in ganglion cells, while feedforward inhibition is the primary regulator of tonic ganglion cell signals.

Ambystoma↗