Synthesis of substituted 3-anilino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ones and their evaluation as cholecystokinin-ligands

3-Amino-1,4-benzodiazepines as well as chemically related diverse amines were prepared from oxazepam and subsequently screened on the cholecystokinin receptor in a radiolabel binding assay. Oxazepam 2 was activated via its 3-chloro-1,4-benzodiazepine intermediate 3 and was reacted with a large series of aliphatic and aromatic amines. The substituted 3-anilino-1,4-benzodiazepine structure was identified as lead structure in a diverse series of 3-amino-1,4-benzodiazepines 4-38 and the full SAR (structure-activity relationship) optimisation provided 3-anilinobenzodiazepines 16-38 with CCK 1 receptor selectivity to CCK 2. The compounds 18, 24, 28 and 33 have shown affinities at the CCK 1 receptor of 11, 10, 11 and 9 nM, respectively. These equipotent CCK 1 ligands were fully evaluated in behaviour pharmacological essays. An antidepressant effect was identified in the tail suspension- and the Porsolt swimming-test. The ED 50 values for 24 and 28 were determined in these assays as 0.46 and 0.49 mg/kg. The mixed antagonist 37 showed in addition to the antidepressant effects anxiolytic properties. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons

Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15–30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage -clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states.

Existence and Uniqueness of Solutions for Partial Differential-Functional Equations of the First Order with Deviating Argument of the Derivative of Unknown Function

We consider the existence and uniqueness problem for partial differential-functional equations of the first order with the initial condition for which the right-hand side depends on the derivative of unknown function with deviating argument.

Cauchy Problem for Differential Equation with Caputo Derivative

The paper is devoted to the study of the Cauchy problem for a nonlinear differential equation of complex order with the Caputo fractional derivative. The equivalence of this problem and a nonlinear Volterra integral equation in the space of continuously differentiable functions is established. On the basis of this result, the existence and uniqueness of the solution of the considered Cauchy problem is proved. The approximate-iterative method by Dzjadyk is used to obtain the approximate solution of this problem. Two numerical examples are given.

Cauchy-Type Problem for Diffusion-Wave Equation with the Riemann-Liouville Partial Derivative

2000 Mathematics Subject Classification: 35A15, 44A15, 26A33

Nonexistence Results of Solutions of Semilinear Differential Inequalities with Temperal Fractional Derivative on the Heinsenberg Group

2000 Mathematics Subject Classification: 26A33, 33C60, 44A15, 35K55

Impulsive Fractional Differential Inclusions Involving the Caputo Fractional Derivative

Mathematics Subject Classification: 26A33, 34A37.

Caputo-Type Modification of the Erdélyi-Kober Fractional Derivative

2000 Math. Subject Classification: 26A33; 33E12, 33E30, 44A15, 45J05

On q–Analogues of Caputo Derivative and Mittag–Leffler Function

Mathematics Subject Classification: 33D60, 33E12, 26A33

Integral Representations of the Logarithmic Derivative of the Selberg Zeta Function

AMS Subj. Classification: MSC2010: 11F72, 11M36, 58J37

An Analog of the Tricomi Problem for a Mixed Type Equation with a Partial Fractional Derivative

Mathematics Subject Classification 2010: 35M10, 35R11, 26A33, 33C05, 33E12, 33C20.

Calculating the derivative of piecewise functions

Exercises involving the calculation of the derivative of piecewise defined functions are common in calculus, with the aim of consolidating beginners’ knowledge of applying the definition of the derivative. In such exercises, the piecewise function is commonly made up of two smooth pieces joined together at one point. A strategy which avoids using the definition of the derivative is to find the derivative function of each smooth piece and check whether these functions agree at the chosen point. Showing that this strategy works together with investigating discontinuities of the derivative is usually beyond a calculus course. However, we shall show that elementary arguments can be used to clarify the calculation and behaviour of the derivative for piecewise functions.

Fiber Scaffolds of Poly (glycerol-dodecanedioate) and its Derivative via Electrospinning for Neural Tissue Engineering

Peripheral nerves have demonstrated the ability to bridge gaps of up to 6 mm. Peripheral Nerve System injury sites beyond this range need autograft or allograft surgery. Central Nerve System cells do not allow spontaneous regeneration due to the intrinsic environmental inhibition. Although stem cell therapy seems to be a promising approach towards nerve repair, it is essential to use the distinct three-dimensional architecture of a cell scaffold with proper biomolecule embedding in order to ensure that the local environment can be controlled well enough for growth and survival. Many approaches have been developed for the fabrication of 3D scaffolds, and more recently, fiber-based scaffolds produced via the electrospinning have been garnering increasing interest, as it offers the opportunity for control over fiber composition, as well as fiber mesh porosity using a relatively simple experimental setup. All these attributes make electrospun fibers a new class of promising scaffolds for neural tissue engineering. Therefore, the purpose of this doctoral study is to investigate the use of the novel material PGD and its derivative PGDF for obtaining fiber scaffolds using the electrospinning. The performance of these scaffolds, combined with neural lineage cells derived from ESCs, was evaluated by the dissolvability test, Raman spectroscopy, cell viability assay, real time PCR, Immunocytochemistry, extracellular electrophysiology, etc. The newly designed collector makes it possible to easily obtain fibers with adequate length and integrity. The utilization of a solvent like ethanol and water for electrospinning of fibrous scaffolds provides a potentially less toxic and more biocompatible fabrication method. Cell viability testing demonstrated that the addition of gelatin leads to significant improvement of cell proliferation on the scaffolds. Both real time PCR and Immunocytochemistry analysis indicated that motor neuron differentiation was achieved through the high motor neuron gene expression using the metabolites approach. The addition of Fumaric acid into fiber scaffolds further promoted the differentiation. Based on the results, this newly fabricated electrospun fiber scaffold, combined with neural lineage cells, provides a potential alternate strategy for nerve injury repair.

A transatlantic case: the derivative action as a corporate governance tool

The derivative action as a minority shareholder protection device seems to be almost a dead-letter law in the British Isles as compared with the United States. Whether it can or should be revived through legislative reform and judicial interpretation presents us with important governance questions at first instance, but also raises questions regarding the importance of law, as distinct from non-legally enforceable norms, to the development of corporate governance systems, in particular regarding the director-shareholder relationship.