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 541 records · Page 30Linked to original sources
PubMed1998

Effects of dialyzing gamma-aminobutyric acid receptor antagonists into the medial preoptic and arcuate ventromedial region on luteinizing hormone release in male sheep.

We investigated the effects of microdialyzing alpha-aminobutyric acid (GABA) receptor antagonists into either the medial preoptic area (mPOA) or the arcuate-ventromedial region (ARC-VMR) on LH secretion. Bicuculline methiodide (BMI, GABA(A) receptor antagonist), and either 2-hydroxysaclofen (SAC) or CGP 55845A (CGP, GABA(B) receptor antagonists) were used. In experiment 1, castrated rams received 4-h dialysis into either the mPOA (n = 5) or ARC-VMR (n = 4) of artificial cerebrospinal fluid (aCSF) followed by 4 h of either BMI (aCSF-BMI, 375 microM in mPOA, 1 mM in the ARC-VMR for 2-1/2 h), or aCSF-SAC (5 mM). In experiment 2, castrated rams received dialysis only in the ARC-VMR (n = 5) of aCSF-aCSF, aCSF-BMI (375 microM), or aCSF-CGP (50 microM). In experiment 3, untreated or testosterone (T)-treated castrated rams (n = 6/group) received dialysis only in the ARC-VMR of aCSF-aCSF, aCSF-BMI (375 microM), or aCSF-CGP (500 microM). Jugular blood was collected at 10-min intervals. In experiment 1, BMI suppressed mean plasma LH (p < 0.05) and increased interpulse interval (IPI, p < 0.05) at both sites. In experiment 2, BMI significantly reduced mean LH and increased IPI (p < 0.01). In experiment 3, BMI reduced mean LH in both the presence (p < 0.05) and absence of T (p < 0.01) and increased IPI (p < 0.01) in the absence of T. SAC, CGP, and aCSF did not affect LH in any experiment. These results show that dialysis of BMI, into either the mPOA or the ARC-VMR of either castrated or T-treated castrated rams decreased LH release, whereas dialysis of GABA(B) antagonists at these sites was without detectable effect.

Animals↗
PubMed1998

Net interaction between different forms of short-term synaptic plasticity and slow-IPSPs in the hippocampus and auditory cortex.

Paired-pulse plasticity is typically used to study the mechanisms underlying synaptic transmission and modulation. An important question relates to whether, under physiological conditions in which various opposing synaptic properties are acting in parallel, the net effect is facilitatory or depressive, that is, whether cells further or closer to threshold. For example, does the net sum of paired-pulse facilitation (PPF) of excitatory postsynaptic potentials (EPSPs), paired-pulse depression (PPD) of inhibitory postsynaptic potentials (IPSPs), and the hyperpolarizing slow IPSP result in depression or facilitation? Here we examine how different time-dependent properties act in parallel and examine the contribution of gamma-aminobutyric acid-B (GABAB) receptors that mediate two opposing processes, the slow IPSP and PPD of the fast IPSP. Using intracellular recordings from rat CA3 hippocampal neurons and L-II/III auditory cortex neurons, we examined the postsynaptic responses to paired-pulse stimulation (with intervals between 50 and 400 ms) of the Schaffer collaterals and white matter, respectively. Changes in the amplitude, time-to-peak (TTP), and slope of each EPSP were analyzed before and after application of the GABAB antagonist CGP-55845. In both CA3 and L-II/III neurons the peak amplitude of the second EPSP was generally depressed (further from threshold) compared with the first at the longer intervals; however, these EPSPs were generally broader and exhibited a longer TTP that could result in facilitation by enhancing temporal summation. At the short intervals CA3 neurons exhibited facilitation of the peak EPSP amplitude in the absence and presence of CGP-55845. In contrast, on average L-II/III cells did not exhibit facilitation at any interval, in the absence or presence of CGP-55845. CGP-55845 generally "erased" short-term plasticity, equalizing the peak amplitude and TTP of the first and second EPSPs at longer intervals in the hippocampus and auditory cortex. These results show that it is necessary to consider all time-dependent properties to determine whether facilitation or depression will dominate under intact pharmacological conditions. Furthermore our results suggest that GABAB-dependent properties may be the major contributor to short-term plasticity on the time scale of a few hundred milliseconds and are consistent with the hypothesis that the balance of different time-dependent processes can modulate the state of networks in a complex manner and could contribute to the generation of temporally sensitive neural responses.

Animals↗
PubMed2006

Characterization of the glycinergic input to bipolar cells of the mouse retina.

Glycine and gamma-aminobutyric acid (GABA) are the major inhibitory transmitters of the mammalian retina, and bipolar cells receive GABAergic and glycinergic inhibition from multiple amacrine cell types. Here we evaluated the functional properties and subunit composition of glycine receptors (GlyRs) in bipolar cells. Patch-clamp recordings were performed from retinal slices of wild-type, GlyRalpha1-deficient (Glra1(spd-ot)) and GlyRalpha3-deficient (Glra3(-/-)) mice. Whole-cell currents following glycine application and spontaneous inhibitory postsynaptic currents (IPSCs) were analysed. During the recordings the cells were filled with Alexa 488 and, thus, unequivocally identified. Glycine-induced currents of bipolar cells were picrotoxinin-insensitive and thus represent heteromeric channels composed of alpha and beta subunits. Glycine-induced currents and IPSCs were absent from all bipolar cells of Glra1(spd-ot) mice, indicating that GlyRalpha1 is an essential subunit of bipolar cell GlyRs. By comparing IPSCs of bipolar cells in wild-type and Glra3(-/-) mice, no statistically significant differences were found. OFF-cone bipolar (CB) cells receive a strong glycinergic input from AII amacrine cells, that is preferentially based on the fast alpha1beta-containing channels (mean decay time constant tau = 5.9 +/- 1.4 ms). We did not observe glycinergic IPSCs in ON-CB cells and could elicit only small, if any, glycinergic currents. Rod bipolar cells receive a prominent glycinergic input that is mainly mediated by alpha1beta-containing channels (tau = 5.5 +/- 1.6 ms). Slow IPSCs, the characteristic of GlyRs containing the alpha2 subunit, were not observed in bipolar cells. Thus, different bipolar cell types receive kinetically fast glycinergic inputs, preferentially mediated by GlyRs composed of alpha1 and beta subunits.

Animals↗
PubMed2004

Mechanism of GABA receptor-mediated inhibition of spontaneous GABA release onto cerebellar Purkinje cells.

gamma-Aminobutyric acid (GABA)(B) receptor-mediated modulation of spontaneous GABA release onto Purkinje cells was investigated in cerebellar slices from 3- to 5-week-old mice. The GABA(B) receptor agonists baclofen and CGP 44533 each reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs), with no significant effect on mIPSC amplitude; together, consistent with a presynaptic site of action. The GABA(B) receptor antagonist CGP 55845 blocked baclofen-induced inhibition. The sulphydryl alkylating agent N-ethylmaleimide occluded baclofen effects, implicating G(i/o) subunits in mediating a GABA(B) G protein-coupled receptor pathway. Baclofen-induced inhibition persisted in the presence of Ba(2+), a blocker of K(+) channels, and Cd(2+), a blocker of Ca(2+) channel-mediated GABA release. Application of nominally Ca(2+)-free extracellular solutions reduced mIPSC frequency and amplitude; however, baclofen produced a significant inhibition in mIPSC frequency, further suggesting that this pathway was independent of Ca(2+) influx. Spontaneous GABA release was increased by the adenylate cyclase activator, forskolin, and the phorbol ester, phorbol 12,13-dibutyrate. However, baclofen-induced inhibition was not significantly changed in either condition. Baclofen action was also not affected by the adenylate cyclase inhibitor SQ 22536 or the protein kinase C inhibitor chelerythrine chloride. Baclofen still reduced mIPSC frequency in the presence of the polyvalent cation ruthenium red, which acts as a secretagogue here; however, baclofen-induced inhibition was reduced significantly. Furthermore, baclofen produced no clear inhibition during high-frequency mIPSCs bursts induced by the potent secretagogue alpha-Latrotoxin. Together, these results suggest that GABA(B) inhibition occurs downstream of Ca(2+) influx and may be mediated, in part, by an inhibition of the vesicular release mechanism.

Action Potentials↗
PubMed2001

Cloning and functional expression of GABA(B) receptors from Drosophila.

The neurotransmitter GABA (gamma-aminobutyric acid) functions as the major inhibitory neurotransmitter in the central nervous system of vertebrates and invertebrates. In vertebrates GABA signals both through ionotropic receptors (GABA(A), GABA(C)), which induce fast synaptic inhibitory responses, and through metabotropic receptors (GABA(B)), which play a fundamental role in the reduction of presynaptic transmitter release and postsynaptic inhibitory potentials. Whilst GABA(A) and GABA(C) receptors have been cloned from vertebrates as well as invertebrates, GABA(B) receptors have only been identified in vertebrate species to date, although indirect evidence suggests their existence in arthropods, too. Here we report the cloning of three putative invertebrate GABA(B) receptor subtypes (D-GABA(B)R1, R2 and R3) isolated from Drosophila melanogaster. Whilst D-GABA(B)R1 and R2 show high sequence identity to mammalian GABA(B)R1 and R2, respectively, the receptor D-GABA(B)R3 seems to be an insect-specific subtype with no known mammalian counterpart so far. All three D-GABA(B)R subtypes are expressed in the embryonic central nervous system. In situ hybridization of Drosophila melanogaster embryos shows that two of the D-GABA(B)Rs (D-GABA(B)R1 and R2) are expressed in similar regions, suggesting a coexpression of the two receptors, whilst the third D-GABA(B)R (D-GABA(B)R3) displays a unique expression pattern. In agreement with these results we have only been able to functionally characterize D-GABA(B)R1 and R2 when the two subtypes are coexpressed either in Xenopus laevis oocytes or mammalian cell lines, whilst D-GABA(B)R3 was inactive in any combination. The pharmacology of the coexpressed D-GABA(B)R1/2 receptor was different from the mammalian GABA(B)Rs: e.g. baclofen, an agonist of mammalian GABA(B)Rs, showed no effect.

Adenylyl Cyclase Inhibitors↗
PubMed1998

Distinct GABAB actions via synaptic and extrasynaptic receptors in rat hippocampus in vitro.

Intracellular recordings were obtained from pyramidal cells to examine gamma-aminobutyric acid-B (GABAB)-mediated synaptic mechanisms in the CA1 region of rat hippocampal slices. To investigate if heterogeneous ionic mechanisms linked to GABAB receptors originate from distinct sets of inhibitory fibers, GABAB-mediated monosynaptic late inhibitory postsynaptic potentials (IPSPs) were elicited in the presence of antagonists of ionotropic glutamate and GABAA receptors and of an inhibitor of GABA uptake and were compared after direct stimulation of inhibitory fibers in three different CA1 layers: stratum oriens, radiatum, and lacunosum-moleculare. No significant differences were found in mean amplitude, rise time, or time to decay to half-amplitude of IPSPs evoked from the three layers. Mean equilibrium potential (Erev) of late IPSPs was similar for all groups and close to the equilibrium potential of K+. Bath application of the GABAB antagonist CGP55845A blocked all monosynaptic late IPSPs. During recordings with micropipettes containing guanosine-5'-O-(3-thiotriphosphate) (GTPgammaS), the mean amplitude of all GABAB IPSPs gradually was reduced. Bath application of Ba2+ completely eliminated monosynaptic late IPSPs evoked from any of the stimulation sites. Late IPSPs were blocked completely during Ba2+ applications that reduced the GABAB-mediated hyperpolarizations elicited by local application of exogenous GABA only by approximately 50%. These results indicate that heterogenous K+ conductances activated by GABAB receptors do not originate from separate sets of inhibitory fibers in these layers. To examine if synchronous release of GABA from a larger number of inhibitory fibers could activate heterogeneous GABAB mechanisms, giant GABAB IPSPs were induced by 4-aminopyridine (4-AP) in the presence of antagonists of ionotropic glutamate and GABAA receptors. The amplitude and time course 4-AP-induced late IPSPs were approximately double that of evoked monosynaptic late IPSPs, but their voltage sensitivity, Erev, and antagonism by the GABAB antagonist CGP55845A and intracellular GTPgammaS were similar. Ba2+ completely abolished 4-AP-induced late IPSPs, whereas responses elicited by exogenous GABA were only reduced by approximately 50% in the same cells. These results indicate that synchronous activation of large numbers of inhibitory fibers, as induced by 4-AP, may not activate heterogenous GABAB-mediated conductances. Similarly, Ba2+ almost completely blocked late inhibitory postsynaptic currents evoked by stimulus trains. Overall, our results show that exogenous GABA can activate heterogenous K+ conductances via GABAB receptors, but that GABA released synaptically, either by electrical stimulation or 4-AP application, can only activate K+ conductances homogeneously sensitive to Ba2+. Thus GABAB receptors located at synaptic and extrasynaptic sites on hippocampal pyramidal cells may be linked to distinct K+ conductances.

4-Aminopyridine↗
PubMed1999

GABA(A) and GABA(B) antagonists differentially affect the firing pattern of substantia nigra dopaminergic neurons in vivo.

The effects of local pressure application of the selective GABA(A) antagonists, bicuculline, gabazine, and picrotoxin, and the selective GABA(B) antagonists, 2-OH-saclofen and CGP-55845A, on the spontaneous activity of electrophysiologically identified substantia nigra dopaminergic neurons were recorded in vivo in urethane anesthetized rats. Blockade of GABA(A) inputs by bicuculline powerfully and reversibly induced burst firing in dopaminergic neurons along with a modest (25%) increase in firing rate, but the increase in burst firing was not correlated with the increase in firing rate. Picrotoxin and gabazine also produced an increase in burst firing without an increase in firing rate. In contrast, local application of GABA(B) antagonists did not produce bursting but rather caused a modest shift to a more regular firing pattern in 50% of the cases. These data demonstrate that dopaminergic neurons in vivo are under tonic GABAergic inhibition mediated by GABA(A) receptors and suggest that GABAergic afferents to substantia nigra comprise a major pathway by which the firing pattern of dopaminergic neurons is controlled in vivo.

Action Potentials↗
PubMed2000

Design and synthesis of an alpha,alpha-difluorophosphinate hapten for antibody-catalyzed hydrolysis of organophosphorus nerve agents.

In a new approach to the safe neutralization of organophosphorus chemical weapons, we designed a hapten to elicit catalytic antibodies with phosphatase activity. Here we report the synthesis of this alpha,alpha-difluorophosphinate hapten 6. Various methods for the introduction of the key alpha,alpha-difluoromethyl feature into the phosphinate hapten are discussed. The best results were obtained with the electrophilic gem-difluorinating agent N-fluorobenzenesulfonimide.

Antibodies, Catalytic↗
PubMed2006

Origin of stereoinduction by chiral aminophosphane phosphinite ligands in enantioselective catalysis: asymmetric hydroformylation.

The origin of stereoinduction by chiral aminophosphane phosphinite (AMPP) ligands in asymmetric hydroformylation was investigated with a theoretical approach. The roles of the stereogenic center at the aminophosphane phosphorus atom (NP*) and of the chirality of the backbone were analyzed by considering three experimentally tested cases: 1) P-stereogenic yielding high ee, 2) P-nonstereogenic yielding low ee, and 3) P-stereogenic yielding low ee. We succeeded in reproducing the experimentally observed trends for the three studied AMPP ligands. Our results indicated that alkene insertion into the rhodium-hydride bond is the selectivity-determining step, and not alkene coordination. Additional calculations on model systems revealed that the different nonbonding weak-type interactions of styrene with the substituents of the NP* stereogenic center in an axial position is responsible for stereodifferentiation. The chirality of the AMPP backbone plays a secondary role. The rationalization of the stereochemical outcome is not straightforward, because two competitive equatorial/axial reaction paths, showing opposite asymmetric induction, must be considered. Construction of stereochemical models and evaluation of stereoinduction for novel ligand systems suggested that two prerequisites are required to improve the performance of AMPP-type ligands in asymmetric hydroformylation: 1) combination of stereorecognition and stereohindrance by substituents at the NP* atom, and 2) more rigid backbones.

Catalysis↗
PubMed2007

Design of a phosphinate-based fluorescent probe for superoxide detection in mouse peritoneal macrophages.

3',6'-Bis(diphenylphosphinyl)fluorescein (PF-1) was synthesized as a highly selective and sensitive fluorescent probe for imaging O(2) (.-) in living cells. The design strategy for the probe was based on the nucleophilic mechanism of O(2) (.-) to mediate deprotection of this probe to give fluorescein. Upon reaction with O(2) (.-), the probe exhibits a strong fluorescence response and high selectivity for O(2) (.-) over other reactive oxygen species and some biological compounds. The phosphinate-based probe, as a new fluorescent reagent, is cell-permeable and can detect micromolar changes of O(2) (.-) concentrations by using confocal microscopy in living cells. The unique combination of good selectivity, high sensitivity, good water solubility, and rapid reactivity establishes the potential value of the probe for facilitating investigations of the generation, metabolism, and mechanisms of superoxide-mediated cellular homeostasis and injury.

Animals↗
PubMed2007

Matrix metalloproteinase 11 (MMP-11; stromelysin-3) and synthetic inhibitors.

Matrix metalloproteinase (MMP)-11, or Stromelysin 3, is a particular member of MMP family, a group of zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling. Despite intense efforts since its first characterization 15 years ago, its role and target substrates in different diseases remain largely unknown. While mice with MMP-11 deficiency display no particular phenotype, analysis of different tumorigenesis models with these mice lead to the conclusion that MMP-11 promotes tumor development. In contrast with other MMPs, MMP-11 is unable to degrade any major extracellular matrix component and unlike most of other MMPs that are secreted as inactive proenzymes and activated extracellularly, MMP-11 is secreted under active form. MMP-11 may thus play a unique role in tissue remodeling processes, including those associated with tumor progression. Although MMP-11 and other MMPs have been considered as promising targets to combat cancer, a first series of clinical trials using broad-spectrum MMP inhibitors have not led to significant therapeutic benefits. These disappointing results highlight the need for better understanding of the exact role played by each MMP during the different stages of tumor progression. Among the different strategies to fill this gap, highly specific MMP inhibitors would be of great value. This review provides an update on the selectivity profile of phosphinic MMP-11 synthetic inhibitors developed and discusses the opportunities and limitations to identify inhibitors able to fully discriminate MMP-11 from the other MMPs.

Animals↗
PubMed1990

Hypophosphite transport in human erythrocytes studied by overdetermined one-dimensional NMR exchange analysis.

The membrane transport kinetics of the disubstituted phosphorus oxyacid, hypophosphite, were studied in human red cells under equilibrium exchange conditions. Hypophosphite is an analogue of both the bicarbonate and phosphate ions and is known to be rapidly transported across the human red cell membrane via the anion transport protein, Band 3. The hypophosphite ion is a particularly useful probe of Band 3-mediated membrane transport as the intracellular and extracellular species occur as distinct resonances in the 31P NMR spectrum; as a result the membrane potential may also be readily inferred. We applied 'overdetermined' one-dimensional exchange analysis to estimate the rates of exchange for influx and efflux. The apparent equilibrium exchange (ee) values Kmee for the hypophosphite efflux and influx were different and while the efflux parameters were not able to be unambiguously defined, the measured apparent influx kinetic transport parameters were Vmaxee = 1600 +/- 190 amol cell-1 s-1, and Kmee = 75 +/- 16 mM.

Anion Exchange Protein 1, Erythrocyte↗
PubMed2002

GABAergic modulation of primary gustatory afferent synaptic efficacy.

Modulation of synaptic transmission at the primary sensory afferent synapse is well documented for the somatosensory and olfactory systems. The present study was undertaken to test whether GABA impacts on transmission of gustatory information at the primary afferent synapse. In goldfish, the vagal gustatory input terminates in a laminated structure, the vagal lobes, whose sensory layers are homologous to the mammalian nucleus of the solitary tract. We relied on immunoreactivity for the GABA-transporter, GAT-1, to determine the distribution of GABAergic synapses in the vagal lobe. Immunocytochemistry showed dense, punctate GAT-1 immunoreactivity coincident with the layers of termination of primary afferent fibers. The laminar nature and polarized dendritic structure of the vagal lobe make it amenable to an in vitro slice preparation to study early synaptic events in the transmission of gustatory input. Electrical stimulation of the gustatory nerves in vitro produces synaptic field potentials (fEPSPs) predominantly mediated by ionotropic glutamate receptors. Bath application of either the GABA(A) receptor agonist muscimol or the GABA(B) receptor agonist baclofen caused a nearly complete suppression of the primary fEPSP. Coapplication of the appropriate GABA(A) or GABA(B) receptor antagonist bicuculline or CGP-55845 significantly reversed the effects of the agonists. These data indicate that GABAergic terminals situated in proximity to primary gustatory afferent terminals can modulate primary afferent input via both GABA(A) and GABA(B) receptors. The mechanism of action of GABA(B) receptors suggests a presynaptic locus of action for that receptor.

Animals↗
PubMed2000

Asymmetric preference of serine proteases toward phosphonate and phosphinate esters.

We have previously reported the asymmetric synthesis of (alpha-aminoalkyl) diphenylphosphonate and phosphinate derivatives designed as inhibitors of chymotrypsin- and elastase-like proteases. This paper reports the first kinetic evaluation of individual epimers of the (alpha-aminoalkyl) diphenylphosphonates as inactivators of chymotrypsin, cathepsin G and neutrophil elastase (HNE). Results show that the (R)-epimers consistently function as more potent irreversible inactivators of their respective target proteases than the corresponding (S)-epimers. Additionally, phosphinate analogues were found to be consistently superior to their diphenylphosphonate counterparts. For example, Cbz. Phe(P)(OPh)-(CH(2))(2)-CO(2)Et inactivates cathepsin G approximately 45-fold more rapidly (k(i)/K(i) = 1.2 x 10(5) M(-1). min(-1)) than the analogous Cbz.Phe(P)(OPh)(2) (2.6 x 10(3) M(-1). min(-1)). Similarly, Cbz.Val(P)(OPh)-(CH(2))(2)-CO(2)Et was found to inactivate HNE some 3-fold more efficiently than Cbz.Val(P)(OPh)(2) (6.5 x 10(3) and 2.0 x 10(3) M(-1). min(-1), respectively).

Cathepsin G↗
PubMedDate not supplied

Effect of cholinesterase inhibitors on synaptic potentials of the frog neuromuscular junction.

The action of neostigmine and armin on the parameters of synaptic potentials of the m. cutaneus pectoris of the frog was investigated. Both drugs caused an approximately equal increase in amplitude of miniature end-plate potentials (MEPP) and end-plate potentials (EPP), and lengthened the rise time and the half-decay time of EPP, but the effect of armin developed faster. The presynaptic action of both inhibitors was demonstrated (an increase in the frequency of MEPP and in the quantum composition of EPP), but it developed much more slowly than the postsynaptic effects; it was more marked in the case of neostigmine. Administration of armin after preliminary contact with neostigmine increased the duration of EPP somewhat, but did not potentiate the presynaptic effects. No significant changes were observed when neostigmine was given after armin. The possible mechanism of the presynaptic effects of the cholinesterase inhibitors is discussed.

Action Potentials↗