Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “PHOSPHINIC ACID”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 739 records · Page 41Linked to original sources
PubMed2001

Phosphinic peptide inhibitors of macrophage metalloelastase (MMP-12). Selectivity and mechanism of binding.

Pseudopeptide inhibitors of MMP-12 with a phosphinic dipeptide G psi[PO(2)H-CH(2)]L covering the P1-P1'- positions originating from a combinatorial solid phase library have been identified and kinetically analysed with respect to binding mechanism and selectivity towards MMP-7, MMP-9, MMP-13 and MMP-14. One compound with a low nanomolar dissociation constant for MMP-12 showed significantly lower affinity towards all other MMPs tested compared to MMP-12. Two compounds showed selectivity against MMP-9, MMP-13 and MMP-14. One additional compound showed selectivity against MMP-7. The selectivity of these compounds could partly be rationalized by analysis of homology models of the enzymes. Truncated versions of one inhibitor spanning P2 to P2', P3 to P2' or P2 to P3' showed that interactions on both the prime and the non-prime side are important for binding. A two-step binding mechanism, with a rate limiting second step, was shown for binding of a tryptophane containing inhibitor to MMP-12 by transient state analysis, using the tryptophane residue of the inhibitor as fluorescent probe.

Animals↗
PubMed1976

[Effect of the cholinesterase inhibitor armin on meuromuscular synapse function of the frog sartorius muscle].

The organophosphurus inhibitor of cholinesterases armin(2-10-9--2-10-4 M) prolonged postjunction potentials and in concentration 2-10-9--2-10-7 M increased the amplitude of miniature end-plate potentials (m. e. p. p. s and quantum content of e.p.p.s. These parameters were increased again after washing. Thus, armin (2-10-9--2-10-7 M) exerts anticholinesterase effect only. In concentrations 2-10-6--2-10-4M, in addition to the anticholinesterase effect, it affects presynaptic membrane and inhibits postsynaptic membrane cholinoreceptors.

Animals↗
PubMedDate not supplied

[Pharmakologic analysis of the interrelationship between long-term and short-term memory in dogs with systems of conditioned reflexes].

It has been shown in experiments on dogs with elaborated integrated systems of conditioned reflexes (by Kupalov method) and choice reactions (by Hunter method); that the physiological mechanisms of short-term and long-term memory are not strictly isolated; they include some common biochemical structures and are interrelated. The action of amizyl or armin on the cholinoreceptors disturbs the short-term memory and some elements of the long-term conditioned memory: the duration of retention of traces from conditioned and unconditioned alimentary stimuli is reduced; regulation of the course of stabilized conditioned stereotypes is disturbed; differentiation and use of previous experience (extraction of data from long-term memory) are impeded.

Animals↗
PubMed1999

Pharmacological isolation of the synaptic and nonsynaptic components of the GABA-mediated biphasic response in rat CA1 hippocampal pyramidal cells.

High-frequency stimulation (HFS) applied to stratum radiatum of a rat hippocampal slice in the presence of ionotropic glutamate receptor antagonists evokes a biphasic GABA(A) receptor-dependent response in CA1 pyramidal neurons, with a brief hyperpolarizing IPSP (hIPSP) followed by a long-lasting depolarization. We show now that it is possible to pharmacologically separate the hIPSP and late depolarization from one another. In neurons intracellularly perfused for 1-2 hr with F(-) as the major anion and no ATP, the hIPSP (and the corresponding current, hIPSC) evoked by HFS was blocked, whereas neither the late depolarization nor its underlying current was attenuated. In contrast, internal perfusion with a high concentration (5 mM) of the impermeant lidocaine derivative QX-314 selectively abolished the depolarizing component of the biphasic response and also strongly reduced depolarizations evoked by extracellular microinjection of K(+). Bath application of quinine (0. 2-0.5 mM) or quinidine (0.1 mM) resulted in a pronounced inhibition of the HFS-induced extracellular K(+) concentration ([K(+)](o)) transient but not of the bicarbonate-dependent alkaline shift in extracellular pH. The attenuation of the [K(+)](o) transient was closely paralleled by a suppression of the HFS-evoked depolarization but not of the hIPSP. Quini(di)ne did not affect depolarizations induced by exogenous K(+) either. These data provide direct pharmacological evidence for the view that the HFS-induced biphasic response of the pyramidal neuron is composed of mechanistically distinct components: a direct GABA(A) receptor-mediated phase, which is followed by a slow, nonsynaptic [K(+)](o)-mediated depolarization. The bicarbonate-dependent, activity-induced [K(+)](o) transient can be blocked by quini(di)ne, whereas its depolarizing action in the pyramidal neuron is inhibited by internal QX-314. The presence of fundamentally distinct components in GABA(A) receptor-mediated actions evoked by HFS calls for further investigations of their functional role(s) in standard experimental maneuvers, such as those used in studies of synaptic plasticity and induction of gamma oscillations.

Adenosine Triphosphate↗
PubMed2000

Putative cortical and thalamic inputs elicit convergent excitation in a population of GABAergic interneurons of the lateral amygdala.

Synaptic circuitry in the rat lateral amygdala (AL) was studied in brain slices using electrophysiological recordings. Electrical stimulation of external and internal capsules evoked an EPSC followed by a sequence of GABA(A) and GABA(B) receptor-mediated IPSC in principal neurons. Paired stimulation of either afferents resulted in a significant reduction ( approximately 45%) of the second GABA(A) receptor-mediated IPSC. A priming stimulation, consisting of a priming pulse to one pathway followed by a pulse to the other pathway, resulted in a strong depression of the second IPSC basically identical to that during paired stimulation. Paired- and primed-pulse depressions were largely relieved by 10 micrometer CGP 55845A, indicating regulation through presynaptic GABA(B) receptors. Furthermore, putative interneurons responded with EPSCs of constant latencies to minimal stimulation of both cortical and thalamic fibers, indicating convergent monosynaptic input. At higher stimulation strength, an approximately 15% reduction of EPSCs occurred in interneurons after paired and primed stimulation, which was not sensitive to CGP 55845A. These findings indicate that a rather homogeneous population of interneurons exists in the AL with respect to their afferent connectivity, in that they receive convergent input through putative thalamic and cortical fibers, both directly and indirectly (through principal neurons), and mediate inhibitory control of postsynaptic principal neurons. This symmetrically built GABAergic circuitry can be of functional significance, given the distinctive role of the two afferent input systems for the mediation of different components of fear responses and the importance of GABAergic mechanisms for limitation of excessive neuronal activity.

Afferent Pathways↗
PubMed2001

Contribution of GABA(A) and GABA(B) receptors to thalamic neuronal activity during spontaneous absence seizures in rats.

The contribution of GABAergic mechanisms in thalamic relay nuclei to spike and wave discharges (SWDs) during spontaneous seizures was assessed using the WAG/Rij strain of rats, an established genetic model of absence epilepsy, in combination with single-unit recordings and microiontophoretic techniques in the ventrobasal thalamic complex in vivo. Spontaneous SWDs occurring on the electroencephalogram at 5-9 Hz were associated with burst firing in thalamocortical neurons, which was phase-locked with the spike component. Microiontophoretic application of the GABA(A) receptor antagonist bicuculline significantly increased the magnitude of SWD-related firing in all tested cells. Application of the GABA(B) receptor antagonist CGP 55845A exerted a statistically insignificant modulatory effect on neuronal activity during spontaneous SWDs but significantly attenuated the bicuculline-evoked aggravation of SWD-related firing. The data indicate that, in thalamocortical neurons, (1) GABA(A) receptor-mediated events are recruited with each SWD, (2) SWD-related activity can be evoked with no significant contribution of GABA(B) receptors, and (3) blockade of GABA(A) receptors potentiates SWD-related activity, presumably through an indirect effect mediated through GABA(B) receptors. These results vote against a predominant or even exclusive contribution of GABA(B) receptors to spontaneous SWDs in thalamic relay nuclei in the WAG/Rij strain, but rather point to a critical role of GABA(A) receptor activation. This conclusion is in support of the view that the two subtypes of GABA receptors play a differential role in fast (5-10 Hz) and slow (3 Hz) spike-wave paroxysms observed during absence seizures.

Action Potentials↗
PubMed2001

RXP 407, a selective inhibitor of the N-domain of angiotensin I-converting enzyme, blocks in vivo the degradation of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro with no effect on angiotensin I hydrolysis.

The phosphinic peptide RXP 407 has recently been identified as the first potent selective inhibitor of the N-active site (domain) of angiotensin-converting enzyme (ACE) in vitro. The aim of this study was to probe the in vivo efficacy of this new ACE inhibitor and to assess its effect on the metabolism of AcSDKP and angiotensin I. In mice infused with increasing doses of RXP 407 (0.1--30 mg/kg/30 min), plasma concentrations of AcSDKP, a physiological substrate of the N-domain, increased significantly and dose dependently toward a plateau 4 to 6 times the basal levels. RXP 407 significantly and dose dependently inhibited ex vivo plasma ACE N-domain activity, whereas it had no inhibitory activity toward the ACE C-domain. RXP 407 (10 mg/kg) did not inhibit the pressor response to an i.v. angiotensin I bolus injection in mice. In contrast, lisinopril infusion (5 and 10 mg/kg/30 min) affected the metabolism of both AcSDKP and angiotensin I. Thus, RXP 407 is the first ACE inhibitor that might be used to control selectively AcSDKP metabolism with no effect on blood pressure regulation.

Angiotensin I↗
PubMed2002

BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran]: a cyclic nucleoside phosphonate with antitumor activity.

Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show that a tetrahydrofuran phosphonate analogue of guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl) tetrahydrofuran (BCH-1868), previously reported as having antiviral activity, also displays antitumor activity. In vitro, BCH-1868 inhibited the proliferation of several murine and human cancer cell lines with IC50s in the microM range independently of the tissue type or the presence of multidrug resistance protein MRP/gp190. In vivo, BCH-1868 was active against a variety of human tumor xenograft models (Caki-1, HT-29, DU 145, COLO 205, and CCRF-CEM). In all tumors tested, a significant tumor growth inhibition was noted at 40-50 mg/kg (daily x 5), but no tumor regression was observed in the settings used. To better understand these results, we partially characterized, at the cellular level, the mechanism of action of this new cyclic nucleoside phosphonate and investigated its pharmacokinetic characteristics in mice. We showed that BCH-1868 exerts its antitumor activity by an inhibitory mechanism at the level of DNA polymerase a, resulting in arrest of DNA synthesis and a block of cell division at the S phase of the cell cycle. Low-circulating plasma concentration (Cmax = 87 microM; area under the curve = 1138 micromol x min/liters; after a bolus i.v. injection of 10 mg/kg) and rapid clearance of the drug (terminal half-life, t1/2 = 16 min) may contribute to the modest antitumor efficacy observed in vivo.

Animals↗
PubMed1977

Anaerobic utilization of phosphite/phosphine as a sole source of phosphorus: implication to growth in the Jovian environment.

The objective of the investigation was to isolate anaerobic micro-organisms which had the ability to utilize inorganic phosphorus in forms other than phosphate. The first part of this investigation was to isolate from Cape Canaveral soil micro-organisms capable of utilizing phosphite as their phosphorus source under anaerobic conditions. In an attempt to demonstrate this ability, a medium was prepared which contained hypophosphite as the phosphorus source. This was inoculated with soil samples, and growth was subcultured at least four times. To verify that these isolates could use hypophosphite, they were inoculated into defined hypophosphite medium, and samples were removed periodically and killed with formalin. Growth was determined by turbidity measurements and the sample was then filtered. The filtrate was separated by chromatography and the total amounts of hypophosphite, phosphate and phosphate in the filtrate were measured. By this procedure it appeared that the hypophosphite level began decreasing after 14 hr of incubation suggesting utilization of the hypophosphite under anaerobic conditions. The third part of this investigation used labeled (32P) hypophosphite in a defined medium; the cells were then lysed and the metabolic compounds separated by the use of paper chromatography and autoradiograms, demonstrating the presence of 32P in intermediate metabolic compounds. Similar investigations are now being performed with phosphine as the phosphorus source.

Anaerobiosis↗
PubMed2003

Kinetic-spectrophotometric determination of propylthiouracil based on its inhibitory effect on the reduction of neutral red by hypophosphite.

A new kinetic-spectrophotometric method for determination of propylthiouracil (PTU) is described. The proposed method is simple, rapid, inexpensive and sensitive for the determination of PTU in pure and tablet forms. This method is based on the inhibitory effect of propylthiouracil on the palladium(II)-catalyzed reaction between neutral red and hypophosphite ions. The effect of various parameters such as: dye, hypophosphite, and Pd(II) concentrations, pH, ionic strength, and temperature were optimized. Two distinct linear calibration graphs were observed in the ranges 0.006-0.033 (n = 6, r = 0.9991) and 0.033-0.300 ppm (n = 10, r = 0.9980). The variable time method was used. The limit of detection was 0.004 ppm. The proposed method was applied for the determination of propylthiouracil in pure and tablet forms.

Calibration↗
PubMed2004

Cytotoxic and genotoxic effects of ss-(triphenylpho-s-phonio)ethyl carboxylate and of N,N'-bis(dihexylphos-phinoylmethyl)-1,4-diaminocyclohexane.

BACKGROUND: Several organophosphorous compounds (OPs) are now being tested therapeutically. Cholinesterase inhibition, which in large doses makes these agents effective pesticides, may also be useful in other doses for treating dementia. Metrifonate, for example, has been used to treat schistosomiasis and is undergoing trials for the treatment of primary degenerative dementia. MATERIAL/METHODS: Here we report the characterization of newly synthesized OPs from the group of phosphobetaines [beta-(triphenylphosphonio)ethyl carboxylate, PB] and of alpha-aminophosphoryl compounds [N,N'-bis(dihexylphosphinoylmethyl)-1,4-diaminocyclohexane, AP] according to their toxic and genotoxic properties determined in prokaryotic and eukaryotic test systems. RESULTS: The absence of toxicity towards Gram-negative bacteria and of genotoxicity in Ames mutagenicity assay and in SOS-chromotest did not exclude the cytotoxic effect of PB towards NIH3T3 mouse fibroblasts, which supports the notion of an extremely diverse interspecies response to OPs. In contrast, AP demonstrated toxic properties detected by antibacterial effect as well as by the inhibition of the proliferation and respiration of fibroblasts. The enzymatic transformation of the compound is necessary to reveal the genotoxic properties of AP. The role of mammalian microsomal enzymes and of bacterial C-P lyase in the formation of AP genotoxic metabolites is under discussion. CONCLUSIONS: Neither toxicity nor genotoxicity of PB was found in bacterial tests. Cytotoxic and mutagenic effects of AP were detected. The data contribute to the investigation of the biological activity of novel organophosphates which could be useful for the future development of OP-based therapeutics.

Animals↗
PubMed1988

The contribution of magnetic susceptibility effects to transmembrane chemical shift differences in the 31P NMR spectra of oxygenated erythrocyte suspensions.

Triethyl phosphate, dimethyl methylphosphonate, and the hypophosphite ion all contain the phosphoryl functional group. When added to an oxygenated erythrocyte suspension, the former compound gives rise to a single 31P NMR resonance, whereas the latter compounds give rise to separate intra- and extracellular 31P NMR resonances. On the basis of experiments with intact oxygenated cell suspensions (in which the hematocrit was varied) and with oxygenated cell lysates (in which the lysate concentration was varied), it was concluded that the chemical shifts of the intra- and extracellular populations of triethyl phosphate differ as a consequence of the diamagnetic susceptibility of intracellular oxyhemoglobin but that this difference is averaged by the rapid exchange of the compound across the cell membrane. The difference in the magnetic susceptibility of the intra- and extracellular compartments contributes to the observed separation of the intra- and extracellular resonances of dimethyl methylphosphonate and hypophosphite. The magnitude of this contribution is, however, substantially less than that calculated using a simple two-compartment model and varies with the hematocrit of the suspension. Furthermore, it is insufficient to fully account for the transmembrane chemical shift differences observed for dimethyl methylphosphonate and hypophosphite. An additional effect is operating to move the intracellular resonances of these compounds to a lower chemical shift. The effect is mediated by an intracellular component, and the magnitude of the resultant chemical shift variations depends upon the chemical structure of the phosphoryl compound involved.

Alcohol Oxidoreductases↗
PubMedDate not supplied

Toxic gases used in the microelectronics industry.

Toxic gases are among the most dangerous materials used in manufacturing semiconductors and related devices. The storage, handling, and disposal of these gases pose a major hazard to workers and to communities located near high-technology companies. It must be anticipated that accidents, acts of terrorism, and natural calamities will result in exposure. Flammability, corrosiveness, and concentration must be considered, as well as the immediate danger to life and known human health effects of the gases used.

Air Pollutants, Occupational↗
PubMedDate not supplied

[Pain-alleviating action of gidifen and its combinations with analgesics].

The analgesic effect of gidifen, a new tranquilizer belonging to the group of organophosphorus compounds, manifests itself in relatively high doses (1/3 of the LD50). The quantitative characteristics of the analgesic action depends on the method for evaluating the analgesic action of the drug. On combined use of gidifen and analgesics applied in a definite dosage range the analgesic effect is potentiated. If the tranquilizer under study is combined with non-narcotic analgesics, the above potentiation is accompanied with an increase in the toxicity and myorelaxant activity of gidifen. On combination of the latter with morphine the parameters under consideration are unchanged. According to the pattern of interaction with analgesics gidifen does not differ in principle from benzodiazepine tranquilizers. However, the drug is not superior to benzodiazepines in this respect.

Analgesics↗