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At least 145 records · Page 8Linked to original sources
PubMed2004

Synthesis of a bifunctional monophosphinic acid DOTA analogue ligand and its lanthanide(III) complexes. A gadolinium(III) complex endowed with an optimal water exchange rate for MRI applications.

A new bifunctional octa-coordinating ligand containing an aminobenzyl moiety, DO3APABn (H4DO3APABn = 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl]phosphinic acid}), has been synthesized. Its lanthanide(III) complexes contain one water molecule in the first coordination sphere. The high-resolution 1H and 31P spectra of [Eu(H2O) (DO3APABn)]- show that the twisted square-antiprismatic form of the complexes is more abundant in respect to the corresponding Eu(III)-DOTA complex. The 1H NMRD and variable-temperature 17O relaxation measurements of [Gd(H2O)(DO3APABn)]- show that the water residence time is short (298tauM = 16 ns) and falls into the optimal range predicted by theory for the attainment of high relaxivities once this complex would be endowed by a slow tumbling rate. The relaxivity (298r1 = 6.7 mM(-1) s(-1) at 10 MHz) is higher than expected as a consequence of a significant contribution from the second hydration sphere. These results prompt the use of [Gd(H2O)(DO3APABn)]- as a building block for the set-up of highly efficient macromolecular MRI contrast agents.

Gadolinium↗
PubMed2004

Synaptic depolarizing GABA Response in adults is excitatory and proconvulsive when GABAB receptors are blocked.

In the presence of 4-aminopyridine, interneurons fire synchronously, causing giant GABA-mediated postsynaptic potentials (GPSPs; GPSCs in voltage clamp) in CA3 pyramidal cells in hippocampal slices from adult guinea pigs. These triphasic GPSPs are composed of a GABA(A)-mediated hyperpolarizing component, a depolarizing component, and a GABA(B)-mediated hyperpolarizing component. We propose that GABA(B) receptors exert control over the postsynaptic depolarizing GABA response. Microelectrode and cell-attached recordings demonstrated that the mean number of action potentials during the depolarizing component of the GPSP increased dramatically in the presence of the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2- hydroxypropyl](phenylmethyl) phosphinic acid (CGP 55845A; P = 0.003 and 0.0005, respectively). Whole cell voltage-clamp recordings showed that the postsynaptic GABA(B) and depolarizing GABA components of the GPSC overlap substantially, allowing the GABA(B)-mediated hyperpolarization to suppress the excitation mediated by the depolarizing GABA component. Further voltage-clamp recordings showed that CGP 55845A increased the duration of the depolarizing GABA component of the GPSC even when the GABA(B) component had already been blocked by internal QX-314, suggesting that CGP 55845A also increased the duration of GABA release. When glutamatergic transmission is intact, GPSPs directly precede epileptiform afterdischarges. We hypothesize that the depolarizing component of the GPSP triggers the epileptiform events and show here that enhancement of the depolarizing component with CGP 55845A increased epileptiform activity. CGP 55845A increased the likelihood of a GPSP triggering an epileptiform event from 32 to 99% (P = 0.0000001), and significantly increased the number of afterdischarges per epileptiform event (P = 0.001). Loss of GABA(B) receptor function is associated with temporal lobe epilepsy in rodents and humans. We show here that GABA(B) receptors exert control over the synaptic depolarizing GABA response and that block of GABA(B) receptors makes the depolarizing GABA response excitatory and proconvulsive.

4-Aminopyridine↗
PubMed2002

An oxyanion-hole selective serine protease inhibitor in complex with trypsin.

p-amidinophenylmethylphosphinic acid (AMPA) was designed, synthesized and crystallized in complex with trypsin to study interactions with the oxyanion hole at the S1 site. In comparison to benzamidine, AMPA shows improved activity, which the crystal structure demonstrates to result from hydrogen bonds between the negatively charged phosphinic acid group and the catalytic residues at the oxyanion hole.

Anions↗
PubMed2004

Cortical injury affects short-term plasticity of evoked excitatory synaptic currents.

The hypothesis that plastic changes in the efficacy of excitatory neurotransmission occur in areas of chronic cortical injury was tested by assessing short-term plasticity of evoked excitatory synaptic currents (EPSCs) in neurons of partially isolated neocortical islands (undercut cortex). Whole cell recordings were obtained from layer V pyramidal neurons of sensorimotor cortical slices prepared from P36-P43 control and undercut rats. AMPA/kainate receptor-mediated EPSCs elicited by stimuli delivered at 40 to 66.7 Hz exhibited more paired-pulse depression (PPD) in undercut cortex than control, the time constant of depression evoked by trains of 20- to 66.7-Hz stimuli was faster, and the steady-state amplitude of EPSCs reached after five to seven EPSCs was lower. An antagonist of the glutamate autoreceptor, group II mGluR, increased the steady-state amplitude of EPSCs from undercut but not control cortex, suggesting that activation of presynaptic receptors by released glutamate is more prominent in undercut cortex. In contrast, the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid had no effect. Increasing [Ca(2+)](o) from 2 to 4 mM increased PPD, with a smaller effect in neurons of the undercut. The I-V relationship of AMPA/kainate receptor-mediated EPSCs was close to linear in both control and undercut neurons, and spermine had no significant effect on the EPSCs, suggesting that decreases in postsynaptic glutamate receptors containing the GluR2 subunit were not involved in the alterations in short-term plasticity. Results are compatible with an increase in the probability of transmitter release at excitatory synapses in undercut cortex due to functional changes in presynaptic terminals.

Animals↗
PubMed1995

The reduction of thymine residues in DNA by the combined action of UV light and hypophosphite.

UV irradiation (lambda = 254 nm) of thymine and uracil in aqueous solution containing salts of phosphinic acid (hypophosphites) results in the formation of the corresponding dihydropyrimidine derivatives. The peculiarities of this new photochemical reaction consist of a specificity towards 2,4-dioxophyrimidines, a high quantum yield and a neutral pH optimum. The quantum yield of photoconversion of thymine at pH 7.0 is equal to 1.9 x 10(-2) in 1 M NaH2PO2; it is diminished to 8.5 x 10(-3) in 0.1 M NaH2PO2. The same decrease in quantum yield with concentration is also found for uracil and uridine; quantum yields of their transformations in 0.1 M NaH2PO2 at pH 7.0 are 6.6 x 10(-2) and 1.5 x 10(-1) respectively. The mild conditions and high quantum yields characteristic of the photoinduced reaction above open up the possibility of obtaining DNA molecules which contain among pyrimidine photoproducts mainly dihydropyrimidine residues. A correlation between various types of thymine modifications in UV-irradiated double-stranded DNA (dimers and dihydrothymidine residues) and the amplitude of the intense negative band in the circular dichroism (CD) spectra specific for DNA liquid crystalline dispersions has been established. A possible application of this base-specific modification to the investigation of nucleic acids is considered.

Circular Dichroism↗
PubMed2002

GABA-B-related activity in processing of transcallosal response in cat motor cortex.

GABA-ergic characteristics of transcallosal (TC) responses were studied with specific antagonists of both GABA-A and GABA-B receptor subtypes. We used a paired-pulse paradigm to get insight into the role of GABA in interhemispheric interactions between motor cortices. 3-Amino-2-(4-chlorophenyl)-propylphosphonic acid (phaclofen) and 3-aminopropyl-diethoxymethyl-phosphinic acid (CGP 35348) were used as GABA-B antagonists and bicuculline methiodide (BMI) was used to block the GABA-A receptor. Although both GABA-A and GABA-B antagonists increased spike discharge upon transcallosal stimulation, in both pyramidal tract and non-pyramidal tract neurons, they had different effects on the responses to the first and second stimuli of paired-pulse stimulation (200 msec interval). Although the inhibition seen with the second stimulus was greatly attenuated by antagonists of the GABA-B receptor, it was maintained in the presence of the GABA-A antagonist. These finding support a presynaptic regulation of callosal transmission by GABA-B receptors in the callosal synapse of the cat motor cortex.

Animals↗
PubMed2002

Central effects of 1,4-butanediol are mediated by GABA(B) receptors via its conversion into gamma-hydroxybutyric acid.

The aliphatic alcohol 1,4-butanediol in converted into gamma-hydroxybutyric acid (GHB) via two enzymatic steps: first, it is oxidised by alcohol dehydrogenase in gamma-hydroxybutyraldehyde; second, the latter is transformed, likely by aldehyde dehydrogenase, into GHB. Initially, the present study compared the sedative/hypnotic effect of GHB and 1,4-butanediol, measured as loss of righting reflex. 1,4-Butanediol was more potent than GHB, presumably because of a more rapid penetration of the blood brain barrier. Further alcohol dehydrogenase inhibitors, 4-methylpyrazole and ethanol, totally prevented the sedative/hypnotic effect of 1,4-butanediol; the aldehyde dehydrogenase inhibitor disulfiram partially blocked the sedative/hypnotic effect of 1,4-butanediol. Finally, the sedative/hypnotic effect of 1,4-butanediol was antagonised by the GABA(B) receptor antagonists, SCH 50911 [(2S)(+)-5,5-dimethyl-2-morpholineacetic acid] and CGP 46381 [(3-aminopropyl)(cyclohexylmethyl)phosphinic acid], but not by the putative GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid), indicating that it is mediated by GABA(B) but not GHB receptors. Taken together, these results suggest that the sedative/hypnotic effect of 1,4-butanediol is mediated by its conversion in vivo into GHB which, in turn, binds to GABA(B) receptors. Accordingly 1,4-butanediol, unlike GHB, failed to displace [(3)H]GHB and [(3)H]baclofen in brain membranes.

Animals↗
PubMed2006

Organogels with Fe(III) complexes of phosphorus-containing amphiphiles as two-component isothermal gelators.

The properties of thermally reversible organogels in which the gelators consist of a phosphonic acid monoester, phosphonic acid, or phosphoric acid monoester and a ferric salt are probed by IR and NMR spectroscopies, optical microscopy, X-ray diffraction, rheology, and light and small-angle neutron scattering (SANS) techniques. This is one of a small number of two-component molecular gelator systems in which gelation can be induced isothermally. The data indicate that complexation between the phosphonate moieties and Fe(III) is accompanied by their in situ polymerization to form self-assembled fibrillar networks that encapsulate and immobilize macroscopically the organic liquid component. From SANS measurements, the cross-sectional radii of the cyclindrical fibers are ca. 15 A. The efficiencies of the gelators (based on the diversity of the liquids gelated, the minimum concentration of gelator required to make a gel at room temperature, and the temporal and thermal stabilities of the gels) have been determined. With a common ferric salt and liquid component, phosphonic acid monoesters are generally more efficient than phosphinic acids or phosphoric acid esters. Of the phosphonic acid monoesters, monophosphonates are better gelator components than bisphosphonates, and introduction of an omega-hydroxy group on the alkyl chain directly attached to phosphorus reduces significantly gelation ability. Several of the gels are stable for very long periods at room temperature. When heated, they revert to sols over wide temperature ranges. The structures of the gelator complexes and the mechanism of their formation and transformation to gels in selected liquids are examined as well.

Journal Article↗
PubMed2001

Treatment of alloy-electroplating wastewater by an automated solvent extraction technique.

Electroplating with highly toxic metals is being gradually replaced by alloy or mixed-metal electroplating. We developed a solvent extraction method for the treatment of waste rinsewater generated in Zn-Co alloy electroplating, based on the studies of the extraction properties. An alkyl ester of an alkylphosphonic acid (PC-88A) or a dialky phosphinic acid (Cyanex 272) was used as the extractant. The two metals were co-extracted into the organic solvent and then separately recovered in a simple process. The feasibility of the process was demonstrated with automated mixer-settler solvent extraction units.

Automation↗
PubMed2006

Density functional theory study of ligand binding on CdSe (0001), (0001), and (1120) single crystal relaxed and reconstructed surfaces: implications for nanocrystalline growth.

To gain a better understanding of the influence of ligand-surface interactions on nanocrystalline growth, periodic density functional theory calculations were employed in the study of the binding of organic ligands on the relaxed nonpolar (1120) and polar Se terminated (0001) surfaces and the relaxed and vacancy and adatom reconstructed Cd terminated (0001) surface. We examined chemisorption properties of phosphine, amine, phosphine oxide, carboxylic acid, and phosphinic acid model ligands, including preferred binding sites and geometries, vibrational frequencies, and binding energetics, and compared findings to intrinsic growth via addition of CdSe molecules or Cd and Se atoms. Our results indicate that binding of the ligands is preferred in the electron-poor 1-fold sites on all surfaces, with secondary coordination of the acidic ligands through the hydroxyl hydrogen to the electron-rich surface sites. In general ligand adsorption directly obstructs binding sites for growth species on the (1120) surface and only indirectly on the two polar surfaces. The order of binding affinities on the (1120) and (0001) surfaces is PH(3) < OPH(3) approximately HCOOH < NH(3) < OPH(2)OH and that on the (0001) surface is OPH(3) approximately HCOOH < OPH(2)OH < NH(3) < PH(3). Our findings corroborate the experimental observation that incorporation of the nonbulky phosphinic acid-type ligands with high affinity and high selectivity for both the (1120) and (0001) surfaces strongly enhances unidirectional growth on the (0001) surface, while incorporation of either bulky ligands or ligands with moderate affinity does not. Higher affinity of all traditionally used ligands for the (1120) surface compared to the (0001) surface also suggests that new ligands should be engineered to achieve the synthesis of novel shapes that require preferential growth on the (1120) surface.

Journal Article↗
PubMed1993

Plasticity of GABAB receptor in rat spinal cord detected by autoradiography.

Prolonged administration of (+/-)-baclofen induces tolerance to its antinociceptive effect in mice. In the present study we compare the effects of 21 days administration of (-)-baclofen or GABAB (gamma-aminobutyric acidB) receptor antagonists, with saline on the density of GABAB receptor binding sites in rat spinal cord using receptor autoradiography. Treatment with (-)-baclofen significantly reduced the number of silver grains (71%) whilst GABAB receptor antagonists, CGP 36742 (3-aminopropyl-n-butyl-phosphinic acid) and CGP 46381 (3-aminopropyl-cyclohexylmethylphosphinic acid), increased the grain count by 114% and 89%, respectively. These data indicate that GABAB receptors in the spinal cord can be influenced by prolonged administration of receptor ligands.

Animals↗
PubMed1995

Phosphinyl acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase.

The rational design, synthesis, and biological activity of phosphonyl- and phosphinyl-linked bisubstrate analog inhibitors of the enzyme Ras farnesyl protein transferase (FPT) are described. The design strategy for these bisubstrate inhibitors involved connection of the critical binding components of the two substrates of FPT (ras protein and farnesyl pyrophosphate, FPP) through a phosphonyl- or phosphinyl-bearing linker. Compound 14, the first example in this series, was found to be a potent FPT inhibitor (I50 = 60 nM). A further 15-fold enhancement in activity was observed upon replacement of the VLS tripeptide sequence in 14 with VVM (15, I50 = 6 nM). The phosphinic acid analog 16 (I50 = 6 nM) was equiactive to phosphonic acid 15. Compounds 14-16 afforded 1000-fold selectivity for FPT against the closely related enzyme geranylgeranyl protein transferase type I, GGT-I [14, I50(GGT-I) = 59 microM; 15 I50(GGT-I) = 10 microM; 16 I50(GGT-I) = 21 microM]. Methyl and POM ester prodrugs 17-19 were prepared and evaluated in whole cell assays and appear to block ras-induced cell transformation, as well as colony formation in soft agar. A distinctive feature of this novel class of potent and selective bisubstrate FPT inhibitors is that they are non-sulfhydryl in nature.

3T3 Cells↗
PubMed1997

Effects of GABAB receptor antagonists on learning and memory retention in a rat model of absence epilepsy.

A variety of animal models of absence epilepsy have been described and among these exists a genetically susceptible strain of rat (genetic absence epilepsy rats of Strasbourg (GAERS)). These rats produce periods of behavioural arrest with simultaneous production of cortical spike and wave discharges (SWD). GABAB receptor antagonists suppress completely the production of these spike and wave discharges. GABAB receptor ligands have also been reported to affect cognitive performance in rodents. The present study examined the cognitive performance of GAERS and the influence of GABAB receptor antagonists on this activity. Rats were injected intraperitoneally once per day with saline or a GABAB receptor antagonist (CGP 36742 (3-amino-propyl-n-butyl-phosphinic acid) 100 mg/kg; CGP 56433 ([3-(1-(S)-[(3-(cyclohexylmethyl)hydroxy phosphinyl]-2-(S) hydroxy propyl] amino]ethyl]benzoic acid) ([3-{1-(S)-[{3-(cyclohexylmethyl)hydroxy phosphinyl]-2-(S) hydroxy propyl] amino]ethyl]benzoic acid) 1 mg/kg or CGP 61334 ([3-({[3-[(diethoxymethyl)hydroxy phosphinyl]propyl] amino}methyl]-benzoic acid (1 mg/kg). A two-way active avoidance test paradigm with negative reinforcement was used. Untreated GAERS performed significantly better than non-epileptic rats (P < 0.05) and this enhancement in cognitive performance was sustained in rats treated with the GABAB receptor antagonists.

Animals↗
PubMed2002

Determination of dissociation constant of phosphinate group in phosphinic pseudopeptides by capillary zone electrophoresis.

Capillary zone electrophoresis (CZE) was used for determination of dissociation constant of phosphinate group in phosphinic pseudopeptides, i.e. peptides where one peptide bond is substituted by phosphinic acid moiety -PO2--CH2-. The dissociation constants were determined for a set of newly synthesized pseudopeptides derived from a structure N-Ac-Val-Ala(psi)(PO2--CH2)Leu-His-NH2 by nonlinear regression of experimentally measured pH dependence of their effective electrophoretic mobilities. CZE experiments were carried out in Tris-phosphate background electrolytes in the pH range 1.4-3.2. The pseudopeptides were synthesized as a mixture of four diastereomers, the separation of which was achieved in most cases. Moreover, differences of the effective mobilities of the pseudopeptide diastereomers enabled simultaneous determination of the dissociation constant of their phosphinate group without necessity of previous isolation of individual isomers.

Electrophoresis, Capillary↗
PubMed1996

Design and in vitro pharmacology of a selective gamma-aminobutyric acidC receptor antagonist.

In mammals, receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are divided into three pharmacological classes, which are denoted GABAA, GABAB, and GABAC. GABAC receptors are defined by their insensitivity to the GABAA receptor antagonist bicuculline and the GABAB receptor agonist (-)-baclofen. GABAC receptors probably are a heterogeneous group of proteins. The most extensively studied mammalian GABAC receptors are those found in neurons of the outer retina. These receptors are GABA-gated Cl- channels comprised of p subunits, of which there are two subtypes. The physiological functions served by GABAC receptors are largely unknown; to determine the functions, it would be useful to have GABAC-selective ligands. In a previous study, we found that isoguvacine, a GABAA-selective agonist, and 3-aminopropyl-(methyl)phosphinic acid (3-APMPA), a GABAB-selective agonist, show affinity for retinal GABAC receptors. In particular, 3-APMPA is an antagonist with low micromolar potency (Kb approximately 1 microM). Here, we report the synthesis and pharmacological characterization of (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), a hybrid of isoguvacine and 3-APMPA designed to retain affinity for GABAC receptors but not to interact with GABAA or GABAB receptors. Electrical assays show that TPMPA is a competitive antagonist of cloned human mu 1 GABAC receptors expressed in Xenopus laevis oocytes (Kb approximately 2 microM). TPMPA is > 100-fold weaker as an inhibitor of rat brain GABAA receptors expressed in oocytes (Kb approximately 320 microM) and has only weak agonist activity on GABAB receptors assayed in rat hippocampal slices (EC50 approximately 500 microM). TPMPA should be a useful pharmacological probe with which to investigate GABAC receptor function in the outer retina and in any other areas of the nervous system in which these types of receptor are present.

Animals↗
PubMed2003

Physicochemical characterization of phosphinic pseudopeptides by capillary zone electrophoresis in highly acidic background electrolytes.

Phosphinic pseudopeptides (i.e., peptide isosteres with one peptide bond replaced by a phosphinic acid moiety) were analyzed and physicochemically characterized by capillary zone electrophoresis in the pH range of 1.1-3.2, employing phosphoric, phosphinic, oxalic and dichloroacetic acids as background electrolyte (BGE) constituents. The acid dissociation constant (pK(a)) of phosphinate group in phosphinic pseudopeptides and ionic mobilities of these analytes were determined from the pH dependence of their effective electrophoretic mobilities corrected to standard temperature and constant ionic strength of the BGEs. It was shown that these corrections are necessary whenever precise mobility data at very low pH are to be determined. Additionally, it was found that the ionic mobilities of the phosphinic pseudopeptides and pK(a) of their phosphinate group are affected by the BGE constituent used. The variability of migration behavior of the pseudopeptides can be attributed to their ion-pairing formation with the BGE components.

Buffers↗
PubMed2002

Component analysis of the commercial metal extractant, Cyanex 302, by GC-MS.

The composition of the commercial reagent Cyanex 302 was investigated by GC-MS. Mass spectrometric studies allowed us to confirm that bis(2,4,4-trimethylpentyl)monothiophosphinic acid is the major compound and that a considerable amount of tris(2,4,4-trimethylpentyl)phosphine oxide is also present. The study also revealed that the extractant has three minor components. These were identified as bis(2,4,4-trimethylpentyl)phosphinic acid, bis(2,4,4-trimethylpentyl)phosphine oxide and bis(2,4,4-trimethylpentyl)dithiophosphinic acid. The mass spectra of these compounds are discussed and some fragmentation processes are postulated.

Journal Article↗