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[reaction: see text] Simple, rapid, and efficient methods for P(1)' diversification of phosphinic peptides have been developed, employing alkylation and Knoevenagel-type condensation reactions with active methylene phosphinic scaffolds, thus leading to a wide variety of diversified phosphinic and dehydrophosphinic peptides.
[formula: see text] 2-Methylaziridine-2-phosphonates were prepared from enantiopure sulfinimines and were demonstrated to be versatile synthetic intermediates for the synthesis of novel alpha-disubstituted and alpha,beta-trisubstituted alpha-aminophosphonate derivatives. The first asymmetric synthesis of both enantiomers of alpha-methylphosphophenylalanine is described.
Synchronized oscillatory activity is generated among visual neurons in a manner that depends on certain key features of visual stimulation. Although this activity may be important for perceptual integration, its functional significance has yet to be explained. Here we find a very strong correlation between synchronized oscillatory activity in a class of frog retinal ganglion cells (dimming detectors) and a well-known escape response, as shown by behavioral tests and multi-electrode recordings from isolated retinas. Escape behavior elicited by an expanding dark spot was suppressed and potentiated by intraocular injection of GABA(A) receptor and GABA(C) receptor antagonists, respectively. Changes in escape behavior correlated with antagonist-evoked changes in synchronized oscillatory activity but not with changes in the discharge rate of dimming detectors. These antagonists did not affect the expanding dark spot-induced responses in retinal ganglion cells other than dimming detectors. Thus, synchronized oscillations in the retina are likely to encode escape-related information in frogs.
Neural activity regulates the number and properties of GABAergic synapses in the brain, but the mechanisms underlying these changes are unclear. We found that blocking spike activity globally in developing hippocampal neurons from rats reduced the density of GABAergic terminals as well as the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Chronic inactivity later in development led to a reduction in the mIPSC amplitude, without any change in GABAergic synapse density. By contrast, hyperpolarizing or abolishing spike activity in single neurons did not alter GABAergic synaptic inputs. Suppressing activity in individual presynaptic GABAergic neurons also failed to decrease synaptic output. Our results indicate that GABAergic synapses are regulated by the level of activity in surrounding neurons. Notably, we found that the expression of GABAergic plasticity involves changes in the amount of neurotransmitter in individual vesicles.
Following from the classical work of Hubel and Wiesel, it has been recognized that the orientation and the on- and off-zones of receptive fields of layer 4 simple cells in the visual cortex are linked to the spatial alignment and properties of the cells in the visual thalamus that relay the retinal input. Here we present evidence showing that the orientation and the on- and off-zones of receptive fields of layer 6 simple cells in cat visual cortex that provide feedback to the thalamus are similarly linked to the alignment and properties of the receptive fields of the thalamic cells they contact. However, the pattern of influence linked to on- and off-zones is phase-reversed. This has important functional implications.
1 The activation of tachykinin NK(1) receptors in the rat spinal cord produced a transient drop in arterial blood pressure followed by a more prolonged pressor effect which is mediated by the stimulation of the sympatho-adrenal system. This study aims at characterizing the spinal mechanism of that initial hypotension occurring in awake unrestrained rats. 2 The initial hypotension (-18+/-2.0 mmHg at 1 min) and the tachycardia (110+/-10 b.p.m.) produced by the intrathecal (i.t.) injection of the stable NK(1) receptor agonist [Sar(9), Met(O(2))(11)]-SP (Sar9, 0.65 nmol) at T-9 spinal cord level was inhibited by the prior injection of 65 nmol LY306740 or LY303870 (NK(1) receptor antagonists). No inhibition was seen when a similar dose of antagonists was given intravenously. 3 The prior i.t. injection of the GABA(B) receptor antagonist CGP52432 (100 nmol) reduced the hypotension evoked by Sar9 (0.65 nmol) and by the GABA(B) receptor agonist baclofen (100 nmol). The GABA(A) receptor antagonist bicuculline (25 nmol, i.t.) was without effect against Sar9, and the GABA(A) agonist muscimol (100 nmol, i.t.) had no cardiovascular effect. 4 The putative involvement of other mediators (dopamine, serotonine, glycine and glutamate) in Sar9-induced hypotension was made unlikely on the basis of various pharmacological treatments. Thus data, suggest that the transient hypotension which occurs upon the activation of NK(1) receptors in the spinal cord is due to the release of GABA which in turn activates GABA(B) receptors to inhibit sympathetic pre-ganglionic fibres. This mechanism may have a physiological significance in the spinal reflex autonomic control of arterial blood pressure.
1. This study examined whether GABA(B) receptor agonists injected directly into the substantia nigra pars reticulata (SNr) and globus pallidus (GP), or given intracerebroventricularly, could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, stereotaxically cannulated above the SNr, GP or third ventricle, were rendered akinetic by injection of reserpine (5 mg kg(-1) s.c.). After 18 h, the locomotor effects of the GABA(B) receptor agonists, baclofen or SKF 97541 were examined. 3. Unilateral injection of baclofen (1-5 micro g in 0.5 micro l) into the GP failed to evoke any locomotor response (n=6). In contrast, unilateral intranigral injection of baclofen (0.08-1.6 micro g in 0.5 micro l) produced a dose-dependent increase in net contraversive rotations reaching a maximum of 162+/-24 turns 90 min(-1) (n=6-8). Pretreatment with the selective GABA(B) receptor antagonist, CGP 46381 (2.4 micro g in 0.5 micro l), inhibited the effects of baclofen (0.8 micro g) by 68+/-9% (n=6). 4. Following intracerebroventricular injection, baclofen (0.8-4 micro g in 2 micro l) produced a dose-dependent increase in net arbitrary locomotor units (ALUs), reaching a maximum of 447+/-154 ALUs in 35 min (n=6-7). SKF 97541 (4-32 micro g in 2 micro l) similarly reversed akinesia, reaching 129+/-69 ALUs in 15 min (n=6). 5. These data show that activation of GABA(B) receptors within the SNr, but not the GP, reverses reserpine-induced akinesia. The success of intracerebroventricular injection of baclofen suggests a potential for systemically active GABA(B) receptor agonists in the treatment of akinesia in Parkinson's disease.
Lanthanide-induced modulation of GABA(C) receptors expressed in Xenopus oocytes was studied. We obtained two-electrode voltage-clamp recordings of ionic currents mediated by recombinant homomeric GABArho(1) receptors and performed numerical simulations of kinetic models of the macroscopic ionic currents.GABA-evoked chloride currents were potentiated by La(3+), Lu(3+) and Gd(3+) in the micromolar range. Lanthanide effects were rapid, reversible and voltage independent. The degree of potentiation was reduced by increasing GABA concentration.Lu(3+) also induced receptor desensitization and decreased the deactivation rate of GABArho(1) currents. In the presence of 300 microM Lu(3+), dose-response curves for GABA-evoked currents showed a significant enhancement of the maximum amplitude and an increase of the apparent affinity. The rate of onset of TPMPA and picrotoxin antagonism of GABArho(1) receptors was modulated by Lu(3+). These results suggest that the potentiation of the anionic current was the result of a direct lanthanide-receptor interaction at a site capable of allosterically modulating channel properties. Based on kinetic schemes, which included a second open state and a nonconducting desensitized state that closely reproduced the experimental results, two nonexclusive probable models of GABArho(1) channels gating are proposed.
BACKGROUND AND PURPOSE: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. EXPERIMENTAL APPROACH: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. KEY RESULTS: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. CONCLUSIONS AND IMPLICATIONS: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.
A kinetic method for the determination of Te based on its inhibitory effect on the PdII-catalysed reaction between pyronine G and H2PO2- is described. The influence of experimental variables on the rate of the process and the potential interfering effect of a large number of ions has been studied. Under the selected experimental conditions: 6 x 10(-5) M pyronine G; 0.6 M H2PO2-; pH 2.6, adjusted with Britton-Robinson buffer; 0.80 microgram ml-1 of PdII; and a temperature of 22 +/- 0.2 degrees C, Te was determined in the concentration range 0.08-0.85 microgram ml-1. The method was applied to the determination of Te in waters and lead concentrates.
Ruthenium(II) complexes can be used to oxidise N-Boc hydroxylamine the the presence of tert-butylhydroperoxide to the corresponding nitroso dienophile, which is trapped using cyclohexa-1,3-diene as the hetero-Diels-Alder adduct; direct evidence has been obtained for the intervention of a triphenylphosphine oxide-stabilised ruthenium(IV) oxocomplex as the catalytically active species.
N-Trimethylsilyl o-methylphenyldiphenylphosphinimine, (o-MeC6H4)PPh2=NSiMe3 (1), was prepared by reaction of Ph2P(Br)=NSiMe3 with o-methylphenyllithium. Treatment of 1 with LiBun and then Me3SiCl afforded (o-Me3SiCH2C6H4)PPh2=NSiMe3 (2). Lithiations of both 1 and 2 with LiBu(n) in the presence of tmen gave crystalline lithium complexes [Li{CH(R)C6H4(PPh(2=NSiMe3)-.tmen](3, R = H; 4, R = SiMe3). From the mother liquor of 4, traces of the tmen-bridged complex [Li{CH(SiMe3)C6H4(PPh2=NSiMe3)-2}]2(mu-tmen) (5) were obtained. Reaction of 2 with LiBun in Et2O yielded complex [Li{CH(SiMe3)C6H4(PPh2=NSiMe3)-2}.OEt2] (6). Reaction of lithiated with Me2SiCl2 in a 2:1 molar ratio afforded dimethylsilyl-bridged compound Me2Si[CH2C6H4(PPh2=NSiMe3)-2]2 (7). Lithiation of 7 with two equivalents of LiBun in Et2O yielded [Li2{(CHC6H4(PPh2=NSiMe3)-2)2SiMe2}.0.5OEt2](8.0.5OEt2). Treatment of 4 with PhCN formed a lithium enamide complex [Li{N(SiMe3)C(Ph)CHC6H4(PPh2=NSiMe3)-2}.tmen] (9). Reaction of two equivalents of 5 with 1,4-dicyanobenzene gave a dilithium complex [{Li(OEt2)2}2(1,4-{C(N(SiMe3)CHC6H4(PPh2=NSiMe3)-2}2C6H4)] (10). All compounds were characterised by NMR spectroscopy and elemental analyses. The structures of compounds 2, 3, 5, 6 and 9 have been determined by single crystal X-ray diffraction techniques.
The reductive coupling of the bridging phosphide and the adjacent [sigma]-alkynyl moieties in [Pt2(mu-P(t)Bu2){mu,eta1:eta2-C(Ph)CH2}(C[triple bond]C-Ph)(CO)(P(t)Bu2H)(Br)] is promoted by bromide abstraction and is reversed by adding N(n)Bu4Br.
Thioether-phosphinite ligands (P-SR, R = Ph, Pr(I) and Me) bearing substituents with different steric demands on the sulfur centre were tested in the rhodium- and iridium-catalysed asymmetric hydrogenation of prochiral olefins. High enantiomeric excesses (up to 96%) and good activities (TOF up to 860 mol product x (mol catalyst precursor x h)(-1)) were obtained for alpha-acylaminoacrylates derivatives. Our results show that enantiomeric excesses depended strongly on the steric properties of the substituent in the thioether moiety, the metal source and the substrate structure. A bulky group in the thioether moiety along with the metal Rh had a positive effect on enantioselectivity. Reaction of these chiral ligands with [M(cod)2]BF4(M = Ir, Rh; cod = 1,5-cyclooctadiene) yielded complexes [M(cod)(P-SR)]BF4, which were present in only one diastereomeric form having the sulfur substituent in a pseudoaxial disposition. The addition of H2 to iridium complexes gave the cis-dihydridoiridium(iii) complexes [IrH2(cod)(P-SR)]BF4. For complexes [IrH2(cod)(P-SPh)]BF4 and [IrH2(cod)(P-SMe)] only one isomer was present in solution. However, for the complex [IrH2(cod)(P-Si-Pr)]BF4, which contained the more hindered substituent on sulfur, two isomers were detected. In all cases there was a pseudoaxial disposition of the sulfur substituents.
We demonstrate quantum mechanically how to resolve enantiomers from an oriented racemic mixture taking advantage of photodissociation. Our approach employs a femtosecond ultraviolet (UV) laser pulse with specific linear polarization achieving selective photodissociation of one enantiomer from a mixture of L and R enantiomers. As a result, the selected enantiomer is destroyed in the electronically excited state while the opposite enantiomer is left intact in the ground state. As an example we use H2POSD which presents axial chirality. A UV pulse excites the lowest singlet excited state which has nsigma* character and is, therefore, strongly repulsive along the P-S bond. The model simulations are performed using wavepackets which propagate on two dimensional potential energy surfaces, calculated along the chirality and dissociation reaction coordinates using the CASSCF level of theory.
A novel "ditopic" ligand containing two monophosphinate triacetate DOTA-like units linked by a thiourea bridge has been synthesized and its complexes with Ln3+ ions (Ln = Y, Eu, Gd, Dy) investigated by NMR spectroscopy and relaxometry. The presence of one water molecule in the first coordination sphere has been determined by the measurement of the dysprosium(III)-induced 17O NMR shifts. The 1H and 31P NMR spectra of the Eu(III) derivative indicate a higher abundance of the fast-exchanging twisted square antiprismatic (m) isomer than the isomeric square antiprismatic (M; m/M = 3:2) complex. The analysis of the 89Y and 13C T1 NMR relaxation times in the Gd(III)/Y(III) mixed complex have provided useful structural information. Values of ca. 6.3 and 8.2 A for the Gd...Y and Gd...C distances, respectively, have been estimated which indicate a rather compact solution structure. This result finds support in the value of the relaxivity whose increase (at 20 MHz and 298 K) on passing from the monomeric (5.7 s(-1) mM(-1)) to the ditopic complex (8.2 s(-1) mM(-1)) can be attributed to the doubling of the inner-sphere term following the doubling of the molecular size. The structural and dynamic relaxivity-controlling parameters were assessed by a simultaneous fitting of the variable temperature 17O NMR and 1H NMRD relaxometric data. The mean water residence lifetime (298tauM) has been found to be 53 ns, one of the shortest values reported for ditopic complexes. The reorientational correlation time is two times longer (298tauR = 183 ps) than the corresponding value of the parent monomeric Gd(III) complex, thus supporting the view of a limited degree of internal rotation. The possible influence of magnetic Gd-Gd coupling has been excluded by a comparison of the 1H NMRD profiles of the homodinuclear Gd(III)/Gd(III) and the heterodinuclear Gd(III)/Y(III) complexes.
The particulate fraction from hen brain was labelled with [3H]di-isopropyl phosphorofluoridate (DiPF) and separated by polyacrylamide-gel electrophoresis. Four radioactive protein bands (1--4) of molecular weights 155000, 92000, 60000, and 30000 were resolved. Most of the labelling of bands 2, 3 and 4 was inhibited by preincubation with Paraoxon. The residue in band 4 was sensitive to pH 5.2. Successive treatments with Paraoxon and pH 5.2 resulted in the abolition of bands 3 and 4. Bands 1 and 2 contained one and two polypeptides respectively, whose labelling was sensitive to Mipafox, but one, in band 2, was sensitive to higher concentrations of Paraoxon. The concentrations of the other two polypeptides were 6.7 and 1.95 pmol of DiPF bound/g of brain in bands 1 and 2 respectively. Both were as sensitive to Mipafox as neurotoxic esterase and were also sensitive to phenyl benzylcarbamate. 4-Nitrophenyl di-n-pentylphosphinate given in vivo inhibited neurotoxic esterase and the labelling of the band-1 polypeptide by 82% and 84% respectively, but inhibited the labelling of the band 2 polypeptide by 51%. The phosphinate in vitro produced 98% inhibition of the labelling of the band-1 polypeptide, with only 26% inhibition of the band-2 polypeptide, under conditions sufficient to inhibit neurotoxic esterase totally. Both neurotoxic esterase and the band-1 polypeptide were found in the forebrain at 1.74-fold their concentration in the rest of the brain, whereas the band-2 polypeptide was uniformly distributed. The evidence indicates that the Mipafox-sensitive polypeptide in band 1 is the [3H]DiPF-labelled active-site subunit of neurotoxic esterase. The catalytic-centre activity of the enzyme for phenyl valerate hydrolysis was found to be 2.6 x 10(5) min-1.
FAH (fumarylacetoacetate hydrolase) catalyses the final step of tyrosine catabolism to produce fumarate and acetoacetate. HT1 (hereditary tyrosinaemia type 1) results from deficiency of this enzyme. Previously, we prepared a partial mimic of the putative tetrahedral intermediate in the reaction catalysed by FAH co-crystallized with the enzyme to reveal details of the mechanism [Bateman, Bhanumoorthy, Witte, McClard, Grompe and Timm (2001) J. Biol. Chem. 276, 15284-15291]. We have now successfully synthesized complete mimics CEHPOBA {4-[(2-carboxyethyl)-hydroxyphosphinyl]-3-oxobutyrate} and COPHPAA {3-[(3-carboxy-2-oxopropyl)hydroxyphosphinyl]acrylate}, which inhibit FAH in slow-onset tight-binding mode with K(i) values of 41 and 12 nM respectively. A high-resolution (1.35 A; 1 A=0.1 nm) crystal structure of the FAH.CEHPOBA complex was solved to reveal the affinity determinants for these compounds and to provide further insight into the mechanism of FAH catalysis. These compounds are active in vivo, and CEHPOBA demonstrated a notable dose-dependent increase in SA (succinylacetone; a metabolite seen in patients with HT1) in mouse serum after repeated injections, and, following a single injection (1 mumol/g; intraperitoneal), only a modest regain of FAH enzyme activity was detected in liver protein isolates after 24 h. These potent inhibitors provide a means to chemically phenocopy the metabolic defects of either HT1 or FAH knockout mice and promise future pharmacological utility for hepatocyte transplantation.