Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances in order to interpret and predict their effects upon humans. Experimental log D7.4, pKa and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3‐hydroxyphenazepam, 4’‐chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam) and compared with values generated by various software packages (ACD/I‐lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I‐LAB returned the most accurate values for log D7.4 and plasma protein binding while ADMET Predictor returned the most accurate values for pKa. Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future ‘training’ of predictive models for these new psychoactive substances

Pulsar science with the Five hundred metre Aperture Spherical Telescope

With a collecting area of 70 000 m^2, the Five hundred metre Aperture Spherical Telescope (FAST) will allow for great advances in pulsar astronomy. We have performed simulations to estimate the number of previously unknown pulsars FAST will find with its 19-beam or possibly 100-beam receivers for different survey strategies. With the 19-beam receiver, a total of 5200 previously unknown pulsars could be discovered in the Galactic plane, including about 460 millisecond pulsars (MSPs). Such a survey would take just over 200 days with eight hours survey time per day. We also estimate that, with about 80 six-hour days, a survey of M31 and M33 could yield 50--100 extra-Galactic pulsars. A 19-beam receiver would produce just under 500 MB of data per second and requires about 9 tera-ops to perform the major part of a real time analysis. We also simulate the logistics of high-precision timing of MSPs with FAST. Timing of the 50 brightest MSPs to a signal-to-noise of 500 would take about 24 hours per epoch.Comment: 9 pages, 10 figures; accepted for publication in A&

The 2000 Periastron Passage of PSR B1259-63

We report here on a sequence of 28 observations of the binary pulsar system PSR B1259-63/SS2883 at four radio frequencies made with the Australia Telescope Compact Array around the time of the 2000 periastron passage. Observations made on 2000 Sep 1 show that the pulsar's apparent rotation measure (RM) reached a maximum of $-14800 \pm 1800$ rad m$^{-2}$, some 700 times the value measured away from periastron, and is the largest astrophysical RM measured. This value, combined with the dispersion measure implies a magnetic field in the Be star's wind of 6 mG. We find that the light curve of the unpulsed emission is similar to that obtained during the 1997 periastron but that differences in detail imply that the emission disc of the Be star is thicker and/or of higher density. The behaviour of the light curve at late times is best modelled by the adiabatic expansion of a synchrotron bubble formed in the pulsar/disc interaction. The expansion rate of the bubble $\sim 12$ km s$^{-1}$ is surprisingly low but the derived magnetic field of 1.6 G close to that expected.Comment: 8 pages, 6 figures, 3 tables, LaTeX (mn.sty). Accepted for publication in the Monthly Notices of the Royal Astronomical Society. Also available at http://astronomy.swin.edu.au/staff/tconnors/publications.htm

Pulsar magnetic alignment and the pulsewidth-age relation

Using pulsewidth data for 872 isolated radio pulsars we test the hypothesis that pulsars evolve through a progressive narrowing of the emission cone combined with progressive alignment of the spin and magnetic axes. The new data provide strong evidence for the alignment over a time-scale of about 1 Myr with a log standard deviation of around 0.8 across the observed population. This time-scale is shorter than the time-scale of about 10 Myr found by previous authors, but the log standard deviation is larger. The results are inconsistent with models based on magnetic field decay alone or monotonic counter-alignment to orthogonal rotation. The best fits are obtained for a braking index parameter n_gamma approximately equal to 2.3, consistent the mean of the six measured values, but based on a much larger sample of young pulsars. The least-squares fitted models are used to predict the mean inclination angle between the spin and magnetic axes as a function of log characteristic age. Comparing these predictions to existing estimates it is found that the model in which pulsars are born with a random angle of inclination gives the best fit to the data. Plots of the mean beaming fraction as a function of characteristic age are presented using the best-fitting model parameters.Comment: 13 pages, 11 figures, Accepted for publication in MNRA

Heartbeat of the Mouse: a young radio pulsar associated with the axisymmetric nebula G359.23-0.82

We report the discovery of PSR J1747-2958, a radio pulsar with period P = 98 ms and dispersion measure DM = 101 pc/cc, in a deep observation with the Parkes telescope of the axially-symmetric "Mouse" radio nebula (G359.23-0.82). Timing measurements of the newly discovered pulsar reveal a characteristic age Pdt/2dP = 25 kyr and spin-down luminosity dE/dt = 2.5e36 erg/s. The pulsar (timing) position is consistent with that of the Mouse's "head". The distance derived from the DM, ~2 kpc, is consistent with the Mouse's distance limit from HI absorption, < 5.5 kpc. Also, the X-ray energetics of the Mouse are compatible with being powered by the pulsar. Therefore we argue that PSR J1747-2958, moving at supersonic speed through the local interstellar medium, powers this unusual non-thermal nebula. The pulsar is a weak radio source, with period-averaged flux density at 1374 MHz of 0.25 mJy and luminosity ~1 mJy kpc^2.Comment: 6 pages, 2 figures, accepted for publication in ApJ Letter

The use of a quantitative structure-activity relationship (QSAR) model to predict GABA-A receptor binding of newly emerging benzodiazepines

The illicit market for new psychoactive substances is forever expanding. Benzodiazepines and their derivatives are one of a number of groups of these substances and thus far their number has grown year upon year. For both forensic and clinical purposes it is important to be able to rapidly understand these emerging substances. However as a consequence of the illicit nature of these compounds, there is a deficiency in the pharmacological data available for these ‘new’ benzodiazepines. In order to further understand the pharmacology of ‘new’ benzodiazepines we utilised a quantitative structure-activity relationship (QSAR) approach. A set of 69 benzodiazepine-based compounds was analysed to develop a QSAR training set with respect to published binding values to GABAA receptors. The QSAR model returned an R2 value of 0.90. The most influential factors were found to be the positioning of two H-bond acceptors, two aromatic rings and a hydrophobic group. A test set of nine random compounds was then selected for internal validation to determine the predictive ability of the model and gave an R2 value of 0.86 when comparing the binding values with their experimental data. The QSAR model was then used to predict the binding for 22 benzodiazepines that are classed as new psychoactive substances. This model will allow rapid prediction of the binding activity of emerging benzodiazepines in a rapid and economic way, compared with lengthy and expensive in vitro/in vivo analysis. This will enable forensic chemists and toxicologists to better understand both recently developed compounds and prediction of substances likely to emerge in the future