Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: Development of a potent and CNS penetrant [3.1.0]-based lead

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]​-​based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclin. model of schizophrenia (prepulse inhibition)​.

On transition rates in surface hopping

Trajectory surface hopping (TSH) is one of the most widely used quantum-classical algorithms for nonadiabatic molecular dynamics. Despite its empirical effectiveness and popularity, a rigorous derivation of TSH as the classical limit of a combined quantum electron-nuclear dynamics is still missing. In this work, we aim to elucidate the theoretical basis for the widely used hopping rules. Naturally, we concentrate thereby on the formal aspects of the TSH. Using a Gaussian wave packet limit, we derive the transition rates governing the hopping process at a simple avoided level crossing. In this derivation, which gives insight into the physics underlying the hopping process, some essential features of the standard TSH algorithm are retrieved, namely (i) non-zero electronic transition rate ("hopping probability") at avoided crossings; (ii) rescaling of the nuclear velocities to conserve total energy; (iii) electronic transition rates linear in the nonadiabatic coupling vectors. The well-known Landau-Zener model is then used for illustration. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4770280]

Hopping conduction and persistent photoconductivity in Cu2ZnSnS4 thin films

The temperature dependence of electrical conductivity and the photoconductivity of polycrystalline Cu2ZnSnS4 were investigated. It was found that at high temperatures the electrical conductivity was dominated by band conduction and nearest-neighbour hopping. However, at lower temperatures, both Mott variable-range hopping (VRH) and Efros–Shklovskii VRH were observed. The analysis of electrical transport showed high doping levels and a large compensation ratio, demonstrating large degree of disorder in Cu2ZnSnS4. Photoconductivity studies showed the presence of a persistent photoconductivity effect with decay time increasing with temperature, due to the presence of random local potential fluctuations in the Cu2ZnSnS4 thin film. These random local potential fluctuations cannot be attributed to grain boundaries but to the large disorder in Cu2ZnSnS4.

Kinetics of layer hopping in a diblock copolymer lamellar phase

In the ordered state, symmetric diblock copolymers self-assemble into an anisotropic lamellar morphology. The equilibrium thickness of the lamellae is the result of a delicate balance between enthalpic and entropic energies, which can be tuned by controlling the temperature. Here we devise a simple yet powerful method of detecting tiny changes in the lamellar thickness using optical microscopy. From such measurements we characterize the enthalpic interaction as well as the kinetics of molecules as they hop from one layer to the next in order to adjust the lamellar thickness in response to a temperature jump. The resolution of the measurements facilitate a direct comparison to predictions from self-consistent field theory.

Spectrum of a Feinberg-Zee random hopping matrix

This paper provides a new proof of a theorem of Chandler-Wilde, Chonchaiya, and Lindner that the spectra of a certain class of infinite, random, tridiagonal matrices contain the unit disc almost surely. It also obtains an analogous result for a more general class of random matrices whose spectra contain a hole around the origin. The presence of the hole forces substantial changes to the analysis.

The chaotic frequency hopping signals for MIMO radar

In multiple-input multiple-output (MIMO) radar systems, the transmitters emit orthogonal waveforms to increase the spatial resolution. New frequency hopping (FH) codes based on chaotic sequences are proposed. The chaotic sequences have the characteristics of good encryption, anti-jamming properties and anti-intercept capabilities. The main idea of chaotic FH is based on queuing theory. According to the sensitivity to initial condition, these sequences can achieve good Hamming auto-correlation while also preserving good average correlation. Simulation results show that the proposed FH signals can achieve lower autocorrelation side lobe level and peak cross-correlation level with the increasing of iterations. Compared to the LFM signals, this sequence has higher range-doppler resolution.

A Hopping Mechanism for Cargo Transport by Molecular Motors on Crowded Microtubules

Most models designed to study the bidirectional movement of cargos as they are driven by molecular motors rely on the idea that motors of different polarities can be coordinated by external agents if arranged into a motor-cargo complex to perform the necessary work Gross, Hither and yon: a review of bidirectional microtubule-based transport (Gross in Phys. Biol. 1:R1-R11, 2004). Although these models have provided us with important insights into these phenomena, there are still many unanswered questions regarding the mechanisms through which the movement of the complex takes place on crowded microtubules. For example (i) how does cargo-binding affect motor motility? and in connection with that-(ii) how does the presence of other motors (and also other cargos) on the microtubule affect the motility of the motor-cargo complex? We discuss these questions from a different perspective. The movement of a cargo is conceived here as a hopping process resulting from the transference of cargo between neighboring motors. In the light of this, we examine the conditions under which cargo might display bidirectional movement even if directed by motors of a single polarity. The global properties of the model in the long-time regime are obtained by mapping the dynamics of the collection of interacting motors and cargos into an asymmetric simple exclusion process (ASEP) which can be resolved using the matrix ansatz introduced by Derrida (Derrida and Evans in Nonequilibrium Statistical Mechanics in One Dimension, pp. 277-304, 1997; Derrida et al. in J. Phys. A 26: 1493-1517, 1993).

The effect of water deprivation on the expression of atrial natriuretic pepide and its receptors in the spinifex hopping mouse, Notomys alexis

This study investigated the mRNA expression of the atrial natriuretic peptide (ANP) system (peptide and receptors) during water deprivation in the spinifex hopping mouse, Notomys alexis, a native of central and western Australia that is well adapted to survive in arid environments. Initially, ANP, NPR-A and NPR-C cDNAs (partial for receptors) were cloned and sequenced, and were shown to have high homology with those of rat and mouse. Using a semi-quantitative multiplex PCR technique, the expression of cardiac ANP mRNA and renal ANP, NPR-A, and NPR-C mRNA was determined in 7- and 14-day water-deprived hopping mice, in parallel with control mice (access to water). The levels of ANP mRNA expression in the heart remained unchanged, but in the kidney ANP mRNA levels were increased in the 7-day water-deprived mice, and were significantly decreased in the 14-day water-deprived mice. NPR-A mRNA levels were significantly higher in 7-day water-deprived mice while no change for NPR-A mRNA expression was observed in 14-day water-deprived mice. No variation in NPR-C mRNA levels was observed. This study shows that water deprivation differentially affects the expression of the ANP system, and that renal ANP expression is more important than cardiac ANP in the physiological adjustment to water deprivation.

Renal C-type natriuretic peptide and natriuretic peptide receptor B mRNA expression are affected by water deprivation in the Spinifex Hopping mouse

This study investigated the effect of water deprivation on the expression of C-type natriuretic peptide (CNP) and natriuretic peptide receptor B (NPR-B) mRNA, and the ability of NPR-B to generate cGMP in the Spinifex Hopping mouse, Notomys alexis. This rodent is a native of central and western Australia that is well adapted to survive in arid environments. Initially, CNP and NPR-B cDNAs (partial for NPR-B) were cloned and sequenced, and were shown to have high homology with those of rat and mouse. RT-PCR analysis showed CNP mRNA expression in the kidney, proximal and distal colon and small intestine, whilst NPR-B mRNA expression was found in the kidney, proximal and distal colon and the atria. Using a semi-quantitative multiplex PCR technique, the expression of renal CNP and NPR-B mRNA was determined in 7- and 14-day water-deprived hopping mice, in parallel with control hopping mice (access to water). Water deprivation significantly decreased the relative levels of CNP and NPR-B mRNA expression in both the 7- and 14-day water-deprived hopping mice, when compared to control hopping mice. In contrast, the ability of CNP to stimulate cGMP production was significantly increased after 14 days of water deprivation. This study shows that alterations in the renal CNP/NPR-B system may be an important physiological adjustment when water is scarce.

Cloning and mRNA expression of guanylin, uroguanylin, and guanylyl cyclase C in the Spinifex hopping mouse, Notomys alexis

Guanylin and uroguanylin are peptides that activate guanylyl cyclase C (GC-C) receptors in the intestine and kidney, which causes an increase in the excretion of salt and water. The Spinifex hopping mouse, Notomys alexis, is a desert rodent that can survive for extended periods without free access to water and it was hypothesised that to conserve water, the expression of guanylin, uroguanylin, and GC-C would be down-regulated to reduce the excretion of water in urine and faeces. Accordingly, this study examined the expression of guanylin, uroguanylin, and GC-C mRNA in Notomys under normal (access to water) and water-deprived conditions. Initially, guanylin and uroguanylin cDNAs encoding the full open reading frame were cloned and sequenced. A PCR analysis showed guanylin and uroguanylin mRNA expression in the small intestine, caecum, proximal and distal colon, heart, and kidney. In addition, a partial GC-C cDNA was obtained and GC-C mRNA expression was demonstrated in the proximal and distal colon, but not the kidney. Subsequently, a semi-quantitative PCR method showed that water deprivation in Notomys caused a significant increase in guanylin and uroguanylin mRNA expression in the distal colon, and in guanylin and GC-C mRNA expression in the proximal colon. No significant difference in guanylin and uroguanylin mRNA expression was observed in the kidney. The results of this study indicate that there is, in fact, an up-regulation of the colonic guanylin system in Notomys after 7 days of water deprivation.

The effect of water deprivation on signalling molecules that utilise cGMP in the Spinifex Hopping Mouse Notomys alexis

In mammals the natriuretic and guanylin peptides influence renal and intestinal fluid content and electrolyte transport by binding to and activating guanylyl cyclase (GC) receptors that in turn stimulate production of the intracellular second messenger guanosine 3':5'-cyclic monophospate
(cGMP). However, the role of natriuretic and guanylin peptides in desert mammals is not understood. The spinifex hopping-mouse (Notomys alexis), has a suite of behavioural and physiological mechanisms that permits survival for extended periods without access to free water. Because signalling molecules that generate cGMP are known to promote water excretion, it was predicted that natriuretic and guanylin peptide synthesis would be down regulated in water-deprived N. alexis, and thus reduce the amount of water lost in the urine and faeces. However, in the kidney ANP and GC-A mRNA levels were increased in water-deprived mice, but CNP and GC-B mRNA levels were decreased. Water deprivation increased guanylin and uroguanylin mRNA expression in the distal colon, but it remained unchanged in the kidney and proximal colon. The expression of GC-C mRNA increased in the proximal colon but not in the distal colon. This study shows that water deprivation differentially affects the expression of regulatory molecules that stimulate cGMP producti

The distribution of renal hyaluronan and the expression of hyaluronan synthases during water deprivation in the Spinifex Hopping Mouse, notomys alexis

Hyaluronan (HA) is a glycosaminoglycan that is synthesized by a family of enzymes called hyaluronan synthases (HASs), of which there are three isoforms (HAS1, 2 and 3) in mammals. The HASs have different tissue expression patterns and function, indicating that synthesis of HA and formation of the HA matrix may be regulated by various factors. The HA matrix has an important role in renal water handling and the production of a concentrated urine. We investigated the distribution of HA and the expression of HAS1, HAS2 and HAS3 mRNAs in the kidney of the Spinifex hopping mouse, Notomys alexis, a native Australian desert rodent that is reported to produce the most concentrated urine of any mammal. After periods of three, seven and fourteen days of water deprivation, the distribution of renal HA changed considerably, and there was a general down-regulation of HAS mRNA expression. It is proposed that the regulation of HA synthesis by the different HAS isoforms during water deprivation in N. alexis, could be influenced by the molecular mass of the HA chains produced by each isoform, followed by the rate at which the individual HAS produces HA.