Inhibition of skeletal muscle sodium currents by Mexiletine analogues: specific hydrophobic interactions rather than lipophilia per se account for drug therapeutic profile

In striated fibers, the activity of mexiletine (Mex)-like sodium channel blockers is strongly modulated by the part of the molecule nearby the asymmetric carbon atom. A lipophilic aromatic phenyl group at this levels, as in 2-(2,6-dimethylphenoxy)-1-phenylethanamine (Me4), markedly increases drug potency, while an increased distance between the stereogenic center and the pharmacophore amino group, as in 3-(2,6-dimethylphenoxy)-2-methylpropan-1-amine (Me2), enhances the use-dependent behavior. In order to better evaluate the role of lipophilicity in drug potency in relation to the structural determinants for a specific binding, lipophilic analogs of Me2 and Me4 were synthesized. Compounds 3-[(2,6-dimethylphenyl) thio]-2-methylpropan-1-amine and 2-[(2,6-dimethylphenyl)thio]-1-phenylethanamine were obtained by isosteric substitution of the oxygen atom with sulfur, while the introduction of a chlorine atom in 4- position of the aryloxy ring lead to 3-(4-chloro-2,6-dimethylphenoxy)-2-methyl-propan-1-amine and 2-(4-chloro-2,6-dimethylphenoxy)-1-phenylethanamine. The compounds were tested on nearly maximal Na+ currents elicited with depolarizing steps at 0.3 Hz (tonic block) and 2-10Hz (use-dependent block) by means of vaseline-gap voltage-clamp method on single frog muscle fibers. The augmented lipophilicity largely increase drug potency in Me2 analogues, the thio and chlorinated compounds being 20- and 10-fold more potent in producing the tonic block, respectively. However, both compounds showed a 2-fold lower use-dependent behavior vs. the high use-dependent Me2. Surprisingly, the same increase in lipophilicity brought about by the same substitutions, in the already high lipophilic and potent Me4 failed to further improve the potency, although both new analogs were more stereoselective than Me4. No correlation was found between logP and potency of all analogs tested. All compounds acted as inactivated channel blockers. In conclusion, lipophilicity differently influences drug profile based on the molecular determinants controlling drug-receptor interaction

Search for standard-model Z and Higgs bosons decaying into a bottom-antibottom quark pair in proton-antiproton collisions at 1.96 TeV

The Collider Detector at Fermilab collected a unique sample of jets originating from bottom-quark fragmentation (b-jets) by selecting online proton-antiproton (pp̄) collisions with a vertex displaced from the pp̄ interaction point, consistent with the decay of a bottom-quark hadron. This data set, collected at a center-of-mass energy of 1.96 TeV, and corresponding to an integrated luminosity of 5.4 fb-1, is used to measure the Z-boson production cross section times branching ratio into bb̄. The number of Z→bb̄ events is determined by fitting the dijet-mass distribution, while constraining the dominant b-jet background, originating from QCD multijet events, with data. The result, σ(pp̄→Z)×B(Z→bb̄)=1.11±0.08(stat)±0.14(syst) nb, is the most precise measurement of this process, and is consistent with the standard-model prediction. The data set is also used to search for Higgs-boson production. No significant signal is expected in our data and the first upper limit on the cross section for the inclusive pp̄→H→bb̄ process at s=1.96 TeV is set, corresponding to 33 times the expected standard-model cross section, or σ=40.6 pb, at the 95% confidence level

Search for standard-model Z and Higgs bosons decaying into a bottom-antibottom quark pair in proton-antiproton collisions at 1.96 TeV

The Collider Detector at Fermilab collected a unique sample of jets originating from bottom-quark fragmentation (b-jets) by selecting online proton-antiproton (p[¯ over p]) collisions with a vertex displaced from the p[¯ over p] interaction point, consistent with the decay of a bottom-quark hadron. This data set, collected at a center-of-mass energy of 1.96 TeV, and corresponding to an integrated luminosity of 5.4  fb[superscript -1], is used to measure the Z-boson production cross section times branching ratio into b[¯ over b]. The number of Z→b[¯ over b] events is determined by fitting the dijet-mass distribution, while constraining the dominant b-jet background, originating from QCD multijet events, with data. The result, σ(p[¯ over p]→Z)×B(Z→b[¯ over b])=1.11 ± 0.08(stat) ± 0.14(syst)  nb, is the most precise measurement of this process, and is consistent with the standard-model prediction. The data set is also used to search for Higgs-boson production. No significant signal is expected in our data and the first upper limit on the cross section for the inclusive p[¯ over p]→H→b[¯ over b] process at √s=1.96  TeV is set, corresponding to 33 times the expected standard-model cross section, or σ=40.6  pb, at the 95% confidence level.National Science Foundation (U.S.)United States. Department of EnergyAlfred P. Sloan Foundatio

Search for the Exotic Meson X(5568) with the Collider Detector at Fermilab

A search for the exotic meson X(5568) decaying into the B[subscript s][superscript 0]π[superscript ±] final state is performed using data corresponding to 9.6  fb[superscript -1] from pp[over ¯] collisions at sqrt[s]=1960  GeV recorded by the Collider Detector at Fermilab. No evidence for this state is found and an upper limit of 6.7% at the 95% confidence level is set on the fraction of B[subscript s][superscript 0] produced through the X(5568)→B[subscript s][superscript 0]π[superscript ±} process

Search for the Exotic Meson X(5568) with the Collider Detector at Fermilab

A search for the exotic meson X(5568) decaying into the Bs0π± final state is performed using data corresponding to 9.6 fb-1 from pp̄ collisions at s=1960 GeV recorded by the Collider Detector at Fermilab. No evidence for this state is found and an upper limit of 6.7% at the 95% confidence level is set on the fraction of Bs0 produced through the X(5568)→Bs0π± process

Tevatron Run II combination of the effective leptonic electroweak mixing angle

Drell-Yan lepton pairs produced in the process pp→â.,"+â.,"-+X through an intermediate γ∗/Z boson have an asymmetry in their angular distribution related to the spontaneous symmetry breaking of the electroweak force and the associated mixing of its neutral gauge bosons. The CDF and D0 experiments have measured the effective-leptonic electroweak mixing parameter sin2θefflept using electron and muon pairs selected from the full Tevatron proton-antiproton data sets collected in 2001-2011, corresponding to 9-10 fb-1 of integrated luminosity. The combination of these measurements yields the most precise result from hadron colliders, sin2θefflept=0.23148±0.00033. This result is consistent with, and approaches in precision, the best measurements from electron-positron colliders. The standard model inference of the on-shell electroweak mixing parameter sin2θW, or equivalently the W-boson mass MW, using the zfitter software package yields sin2θW=0.22324±0.00033 or equivalently, MW=80.367±0.017 GeV/c2

Search for B-s(0) -> mu(+) mu(-) and B-0 -> mu(+) mu(-) decays with the full CDF Run II data set (vol 87, 072003, 2013)

Erratum: Search for Bs0 →μ+μ- and B0 →μ+μ- decays with the full CDF Run II data set (Physical Review D (2013) 87 (072003

Observation of the Production of a W Boson in Association with a Single Charm Quark

The first observation of the production of a W boson with a single charm quark (c) jet in p (p) over bar collisions at root s = 1.96 TeV is reported. The analysis uses data corresponding to 4.3 fb(-1), recorded with the CDF II detector at the Fermilab Tevatron. Charm quark candidates are selected through the identification of an electron or muon from charm-hadron semileptonic decay within a hadronic jet, and a Wc signal is observed with a significance of 5.7 standard deviations. The production cross section sigma(Wc) (p(Tc) > 20 GeV/c, vertical bar eta(c)vertical bar < 1.5) x B(W -> l nu) is measured to be 13.6(-3.1)(+3.4) pb and is in agreement with theoretical expectations. From this result the magnitude of the quark-mixing matrix element V-cs is derived, vertical bar V-cs vertical bar = 1.08 +/- 0.16 along with a lower limit of vertical bar V-cs vertical bar > 0.71 at the 95% confidence level, assuming that the Wc production through c to s quark coupling is dominant. DOI: 10.1103/PhysRevLett.110.07180