The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

We present a new analysis of the lithospheric architecture of Africa, and its evolution from ca. 3.6 Ga to the present. Upperlithosphere domains, generated or reworked in different time periods, have been delineated by integrating regional tectonics and geochronology with geophysical data (magnetic, gravity, and seismic). The origins and evolution of lower-lithosphere domains are interpreted from a high-resolution global shear-wave tomographic model, using thermal/compositional modeling and xenolith/ xenocryst data from volcanic rocks. These data are integrated to map the distribution of Begg et al. 24 Geosphere, February 2009 only the latest stage in this process. The less depleted SCLM that underlies some accretionary belts may have been generated in Archean time, and repeatedly refertilized by the passage of magmas during younger tectonic events. Our analysis indicates that originally Archean SCLM is far more extensive beneath Africa than previously recognized, and implies that post-Archean SCLM rarely survives the collision/accretion process. Where continental crust and SCLM have remained connected, there is a strong linkage between the tectonic evolution of the crust and the composition and modifi cation of its underlying SCLM.

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Conventional spectral T e studies use the real part of the admittance between gravity anomalies and topography or alternatively the square of the magnitude of the coherency (i.e., coherence). Here we show the utility of treating both the admittance and coherency as complex quantities. Inverting the real parts to estimate T e , we use the imaginary parts to tell if the inversion is biased by noise. One method inverts the square of the real coherency, with the internal-to-total load ratio F derived (as a function of wave number) directly from the gravity and topography. The other method inverts the real part of the admittance assuming that F is wave number-independent.We test the methods using synthetic elastic plate models loaded at the surface and Moho in such a way that the final relief is the actual North American topography. In some of the models, we add gravity noise generated by a model having both surface and internal loads such that the final topography is zero, and find that both methods are susceptible to noise. Application of the two methods to North America gives T e maps showing substantial agreement except in regions affected by noise, but these are not a dominant part of the total area. Given the suggested mechanisms by which noise might arise, it is not surprising that it is not a more widespread feature of the North American craton. Importantly, both methods show that large parts of the Canadian Shield are characterised by T e > 100 km. 2 IntroductionThe effective elastic thickness (T e ) of the lithosphere is a convenient measure of the flexural rigidity (D), which is the resistance to bending under applied loads. The two are related by the equation: where the elastic constants E and V are Young's modulus and Poisson's ratio, respectively (see Table 1). In general, T e does not correspond to a physical depth, but rather represents the integrated brittle, elastic and ductile strength of the lithosphere (Watts and Burov, 2003). That is, while the real lithosphere comprises materials of varying rheologies, Burov and Diament (1995) demonstrated that T e is a valid measure of the flexural rigidity for any rheology. Since T e governs many dynamic properties of the Earth, for instance subduction and orogenesis, glacial isostatic adjustment, and stratigraphy (e.g., Watts, 2001), it is an important parameter; however its magnitude over the continents is currently the subject of much controversy.T e is commonly estimated through spectral analysis of gravity and topography data. In one approach, the admittance (Q) is used, while another employs the coherence (J 2 ).The admittance is the wave number (k) domain transfer function between gravity (G) and topography (H). Here capitals indicate either Fourier or wavelet transforms. Thus:where the * indicates complex conjugation, and the angular brackets indicate an averaging process described in Section 4.1. The coherence between gravity and 3 topography gives an indication of their statistical relationship, and is computed through the formula:The gravit...

[1] A variety of methods exist to estimate the elastic thickness (T e ) of the lithosphere. In this contribution, we attempt to provide an indication of how well the fan wavelet coherence method recovers T e , through synthetic modeling. The procedure involves simulating initial topographic and subsurface loads and emplacing them on a thin elastic plate of known T e , generating the postloading topography and gravity. We then attempt to recover that T e distribution from the gravity and topography through the wavelet method, hence discovering where its strengths and weaknesses lie. The T e distributions we use here have elliptical and fractal geometries, while the initial loads are fractal. Importantly, we have found that this widely used synthetic loading calibration method will tend to result in underestimates of T e no matter which recovery method is used. This is due to random correlations between the initial loads which, on average, serve to increase their coherence at all wavelengths and spatial locations. For the fan wavelet method, the degree of underestimation from this ''background'' source is approximately 10% of the true T e . In addition, the fan wavelet coherence method will provide underestimates of (1) the true T e when the study area size is of the order of the highest flexural wavelength or less, (2) relative T e differences when the T e anomaly is narrow compared to its flexural wavelength, and (3) steep T e gradients. Significantly, we find that the recovery is not greatly affected by the assumption of uniform T e in the inversion of the coherence. We also find that T e recovery from the coherence is only weakly dependent upon the initial subsurface-to-surface loading ratio ( f ). In contrast to the coherence, T e recovery from the admittance is highly ''noisy,'' with discontinuities and overestimates of T e frequently arising. This is most likely due to the high sensitivity of the admittance to f and is likely to apply to real data as well.

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Rapid yet accurate pK prediction for druglike molecules is a key challenge in computational chemistry. This study uses PM6-DH+/COSMO, PM6/COSMO, PM7/COSMO, PM3/COSMO, AM1/COSMO, PM3/SMD, AM1/SMD, and DFTB3/SMD to predict the pK values of 53 amine groups in 48 druglike compounds. The approach uses an isodesmic reaction where the pK value is computed relative to a chemically related reference compound for which the pK value has been measured experimentally or estimated using a standard empirical approach. The AM1- and PM3-based methods perform best with RMSE values of 1.4-1.6 pH units that have uncertainties of ±0.2-0.3 pH units, which make them statistically equivalent. However, for all but PM3/SMD and AM1/SMD the RMSEs are dominated by a single outlier, cefadroxil, caused by proton transfer in the zwitterionic protonation state. If this outlier is removed, the RMSE values for PM3/COSMO and AM1/COSMO drop to 1.0 ± 0.2 and 1.1 ± 0.3, whereas PM3/SMD and AM1/SMD remain at 1.5 ± 0.3 and 1.6 ± 0.3/0.4 pH units, making the COSMO-based predictions statistically better than the SMD-based predictions. For pK calculations where a zwitterionic state is not involved or proton transfer in a zwitterionic state is not observed, PM3/COSMO or AM1/COSMO is the best pK prediction method; otherwise PM3/SMD or AM1/SMD should be used. Thus, fast and relatively accurate pK prediction for 100-1000s of druglike amines is feasible with the current setup and relatively modest computational resources.

The synthesis and biochemical evaluation of a series of oxadiazole derivatives of imidazobenzodiazepines related to the benzodiazepine antagonist Ro 15-1788 (2a) are reported. Although the oxadiazole ring is seen as an isosteric replacement for the ester linkage, significant differences in structure-activity trends were observed. Specifically, oxadiazoles 9-12 invariably had increased receptor efficacy (as witnessed by measurements of the GABA shift) relative to the corresponding ester. Additionally, and in direct contrast to the classical agonists such as diazepam, affinity for the benzodiazepine receptor was enhanced by a 7- rather than 8-halo substituent. The results are discussed in terms of a six-point receptor-binding model originally based on the X-ray structure of 2a. For comparison, the crystal structures of two representative oxadiazole derivatives, 10h and 12o, having a 6-oxo and 6-phenyl group, respectively, were determined and the data incorporated into a modified binding model to account for the greater efficacy of these compounds. It is concluded that the antagonist behavior of 2a relies upon the hydrogen-bond-acceptor properties of the ester carbonyl oxygen whereas for the oxadiazole series this site is localized at the imidazole nitrogen.