The Effect of High-Intensity Accelerations and Decelerations on Match Outcome of an Elite English League Two Football Team.

OBJECTIVES: Previous research has highlighted the frequency of high-intensity accelerations and decelerations in elite football. The influence of these actions on match performance outcomes has not been established. The aim of the present study was to identify the influence of high-intensity accelerations and decelerations on match performance outcomes (i.e., win, draw, lost). Comparisons were also made between team and positional high-intensity accelerations and decelerations recorded within the games. METHODS: 26 elite outfield footballers from an elite English Football League (EFL) Two team completed the present study. Global Positioning System (GPS) technology was utilised to quantify high-intensity accelerations and decelerations during 45 games in a competitive season. Magnitude analysis and the effects of results, positions and fixture periods were observed. RESULTS: Significant effects of results, periods and positions were observed (p ≤ 0.05), with the highest outputs observed in games won. Positionally, fullbacks and centre forwards in a 4-3-3 formation exhibited the greatest frequency of high-intensity accelerations and decelerations. Very large differences were observed between the frequency of high-intensity decelerations compared to accelerations in games won (g = 2.37), drawn (g = 2.99) and lost (g = 3.59). The highest team frequencies of high-intensity accelerations (n = 3330) and decelerations (n = 6482) were completed in games won. CONCLUSIONS: The frequency of high-intensity accelerations and decelerations has a significant impact on match performance outcomes in an elite English League Two football team. Consideration needs to be given to specific conditioning and recovery strategies to optimise high-intensity acceleration and deceleration performance in games. Caution should be taken as these findings are representative of one team within the EFL.

Synthesis of a Series of Novel 3,9-Disubstituted Phenanthrenes as Analogues of Known NMDA Receptor Allosteric Modulators.

9-Substituted phenanthrene-3-carboxylic acids have been reported to have allosteric modulatory activity at the NMDA receptor. This receptor is activated by the excitatory neurotransmitter L-glutamate and has been implicated in a range of neurological disorders such as schizophrenia, epilepsy and chronic pain and neurodegenerative disorders such as Alzheimer's disease. Herein, the convenient synthesis of a wide range of novel 3,9-disubstituted phenanthrene derivatives starting from a few common intermediates is described. These new phenanthrene derivatives will help to clarify the structural requirements for allosteric modulation of the NMDA receptor.

Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors.

Competitive N-methyl-d-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N(1)-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype selectivity among the more distantly related kainate receptor family. Compounds 18i and (-)-4 were the most potent kainate receptor antagonists, and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/kg ip) showed antinociceptive effects in an animal model of mild nerve injury.

Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid.

Over-activation of N-methyl-d-aspartate (NMDA) receptors is critically involved in many neurological conditions, thus there has been considerable interest in developing NMDA receptor antagonists. We have recently identified a series of naphthoic and phenanthroic acid compounds that allosterically modulate NMDA receptors through a novel mechanism of action. In the present study, we have determined the structure-activity relationships of 18 naphthoic acid derivatives for the ability to inhibit the four GluN1/GluN2(A-D) NMDA receptor subtypes. 2-Naphthoic acid has low activity at GluN2A-containing receptors and yet lower activity at other NMDA receptors. 3-Amino addition, and especially 3-hydroxy addition, to 2-naphthoic acid increased inhibitory activity at GluN1/GluN2C and GluN1/GluN2D receptors. Further halogen and phenyl substitutions to 2-hydroxy-3-naphthoic acid leads to several relatively potent inhibitors, the most potent of which is UBP618 (1-bromo-2-hydroxy-6-phenylnaphthalene-3-carboxylic acid) with an IC(50) âˆ¼ 2 µM at each of the NMDA receptor subtypes. While UBP618 is non-selective, elimination of the hydroxyl group in UBP618, as in UBP628 and UBP608, leads to an increase in GluN1/GluN2A selectivity. Of the compounds evaluated, specifically those with a 6-phenyl substitution were less able to fully inhibit GluN1/GluN2A, GluN1/GluN2B and GluN1/GluN2C responses (maximal % inhibition of 60-90%). Such antagonists may potentially have reduced adverse effects by not excessively blocking NMDA receptor signaling. Together, these studies reveal discrete structure-activity relationships for the allosteric antagonism of NMDA receptors that may facilitate the development of NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions.

Mapping the ligand binding sites of kainate receptors: molecular determinants of subunit-selective binding of the antagonist [3H]UBP310.

Kainate receptors (KARs) modulate synaptic transmission and plasticity, and their dysfunction has been linked to several disease states such as epilepsy and chronic pain. KARs are tetramers formed from five different subunits. GluK1-3 are low affinity kainate binding subunits, whereas GluK4/5 bind kainate with high affinity. A number of these subunits can be present in any given cell type, and different combinations of subunits confer different properties to KARs. Here we report the characterization of a new GluK1 subunit-selective radiolabeled antagonist (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxythiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione ([(3)H]UBP310) using human recombinant KARs. [(3)H]UBP310 binds to GluK1 with low nanomolar affinity (K(D) = 21 ± 7 nM) but shows no specific binding to GluK2. However, [(3)H]UBP310 also binds to GluK3 (K(D) = 0.65 ± 0.19 µM) but with ~30-fold lower affinity than that observed for GluK1. Competition [(3)H]UBP310 binding experiments on GluK1 revealed the same rank order of affinity of known GluK1-selective ligands as reported previously in functional assays. Nonconserved residues in GluK1-3 adjudged in modeling studies to be important in determining the GluK1 selectivity of UBP310 were point-mutated to switch residues between subunits. None of the mutations altered the expression or trafficking of KAR subunits. Whereas GluK1-T503A mutation diminished [(3)H]UBP310 binding, GluK2-A487T mutation rescued it. Likewise, whereas GluK1-N705S/S706N mutation decreased, GluK3-N691S mutation increased [(3)H]UBP310 binding activity. These data show that Ala487 in GluK2 and Asn691 in GluK3 are important determinants in reducing the affinity of UBP310 for these subunits. Insights from these modeling and point mutation studies will aid the development of new subunit-selective KAR antagonists.

A novel family of negative and positive allosteric modulators of NMDA receptors.

The N-methyl-D-aspartate (NMDA) receptor family regulates various central nervous system functions, such as synaptic plasticity. However, hypo- or hyperactivation of NMDA receptors is critically involved in many neurological and psychiatric conditions, such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Consequently, subtype-selective positive and negative modulators of NMDA receptor function have many potential therapeutic applications not addressed by currently available compounds. We have identified allosteric modulators with several novel patterns of NMDA receptor subtype selectivity that have a novel mechanism of action. In a series of carboxylated naphthalene and phenanthrene derivatives, compounds were identified that selectively potentiate responses at GluN1/GluN2A [e.g., 9-iodophenanthrene-3-carboxylic acid (UBP512)]; GluN1/GluN2A and GluN1/GluN2B [9-cyclopropylphenanthrene-3-carboxylic acid (UBP710)]; GluN1/GluN2D [3,5-dihydroxynaphthalene-2-carboxylic acid (UBP551)]; or GluN1/GluN2C and GluN1/GluN2D receptors [6-, 7-, 8-, and 9-nitro isomers of naphth[1,2-c][1,2,5]oxadiazole-5-sulfonic acid (NSC339614)] and have no effect or inhibit responses at the other NMDA receptors. Selective inhibition was also observed; UBP512 inhibits only GluN1/GluN2C and GluN1/GluN2D receptors, whereas 6-bromo-2-oxo-2H-chromene-3-carboxylic acid (UBP608) inhibits GluN1/GluN2A receptors with a 23-fold selectivity compared with GluN1/GluN2D receptors. The actions of these compounds were not competitive with the agonists L-glutamate or glycine and were not voltage-dependent. Whereas the N-terminal regulatory domain was not necessary for activity of either potentiators or inhibitors, segment 2 of the agonist ligand-binding domain was important for potentiating activity, whereas subtype-specific inhibitory activity was dependent upon segment 1. In terms of chemical structure, activity profile, and mechanism of action, these modulators represent a new class of pharmacological agents for the study of NMDA receptor subtype function and provide novel lead compounds for a variety of neurological disorders.

High-temperature single-site ethylene polymerization behavior of titanate complexes supported by 1,3-bis(3,5-dialkylpyrazol-1-yl)propan-2-olate ligation.

Titanate(1-) complexes Na[(THF)(kappa1-O-bdbpzp)TiCl4] (1) and Na[(THF)(kappa1-O-bdmpzp)TiCl4] (2) and titanate(2-) complexes [Na(THF)]2[(kappa1-O-bdbpzp)2TiCl4] (4) and [Na(THF)]2[(kappa1-O-bdmpzp)2TiCl4] (5) were obtained in good yield from reaction of Na[bdbpzp] or Na[bdmpzp] (sodium salt of 1,3-bis(3,5-di-tert-butylpyrazol-1yl)propan-2-ol or 1,3-bis(3,5-dimethylpyrazol-1yl)propan-2-ol) with TiCl4 (in the appropriate molar ratio) at 0-25 degrees C. Protonolysis of TiCl4 with 1 equiv of bdmpzpH furnished related zwitterionic titanate(1-) complex 3 that possessed a kappa2-N,O-coordinated pyrazolyl-alkoxide with pendant pyrazolium group. Methylalumoxane (MAO) activation of 1-5 under high-temperature solution polymerization conditions produced active single-site ethylene polymerization catalysts that exhibit considerably higher thermal stability (especially 2/MAO, 3/MAO, and 5/MAO) than previously reported for Cp2TiCl2/MAO or Ti catalysts supported by related heteroscorpionate or scorpionate ligation.

A soluble-polymer system for the asymmetric transfer hydrogenation of ketones.

The appropriate combination of methacrylate polymers permits the synthesis of a soluble polymer for use in ruthenium(II)-catalyzed asymmetric transfer hydrogenation reactions. Using a 7:3 copolymer of a poly(ethylene glycol) ester and a hydroxyethyl ester, a derived ruthenium(II)/norephedrine complex catalyses reduction of acetophenone in up to 95% yield and 81% ee.