Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that ...selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial mass screening and subsequent SAR studies have identified 6b (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC50 values of 0.14 and 100 μM against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.18 μM and inhibited COX-1 activity in platelets with an IC50 of 3.1 μM. The choline salt of compound 6b was also orally active in vivo with an ED40 of 7.1 mg/kg in the carrageenan footpad edema (CFE) assay. In vivo studies in rats at a dose of 100 mg/kg showed that this compound inhibited gastric prostaglandin E2 (PGE2) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes.
A semiautomated device for solubility measurements in solution volumes as low as 1 mL was developed for pharmaceutical applications. The device operates nonisothermally, and can measure multiple ...samples simultaneously. Solubilities of model compounds such as paracetamol, mannitol, adipic acid, and glycine were measured and showed a maximum deviation of 5 wt % compared to literature data. Extrapolation of solubility data in the form of activity coefficients was found in good agreement with the literature value over a wide range of temperatures for paracetamol in 2-propanol and adipic acid in ethanol, while some deviation was observed for mannitol in water. The use of the solubility-measuring device to perform solvent screening on multiple solvents for early-stage pharmaceutical compounds was also examined. Results indicate that the slope of the solubility curve with temperature can be estimated with limited data for multiple solvents.
It is well established that the hippocampal formation is critically involved in the acquisition of trace memories, a paradigm in which the conditioned (CS) and unconditioned stimuli (US) are ...separated by a temporal gap (Solomon et al., 1986). The structure is reportedly not critical for the acquisition of delay memories, where the CS and the US overlap in time (Berger & Orr, 1983; Schmaltz & Theios, 1972). Based on these results, it is often stated that the hippocampus is involved in “filling the gap” or otherwise associating the two stimuli in time. However, in addition to the presence of a temporal gap, there are other differences between trace and delay conditioning. The most apparent difference is that animals require many more trials to learn the trace task, and thus it is inherently more difficult than the delay task. Here, we tested whether the hippocampus was critically involved in delay conditioning, if it was rendered more difficult such that the rate of acquisition was shifted to be analogous to trace conditioning. Groups of rats received excitotoxic lesions to the hippocampus, sham lesions or were left intact. Using the same interstimulus intervals (ISI), control animals required more trials to acquire the trace than the delay task. As predicted, animals with hippocampal lesions were impaired during trace conditioning but not delay conditioning. However, when the delay task was rendered more difficult by extending the ISI (a long delay task), animals with hippocampal lesions were impaired. In addition, once the lesioned animal learned the association between the CS and the US during delay conditioning, it could learn and perform the trace CR. Thus, the role of the hippocampus in classical conditioning is not limited to learning about discontiguous events in time and space; rather the structure can become engaged simply as a function of task difficulty.
Exposure to an acute stressful experience facilitates classical conditioning in male rats but impairs conditioning in female rats (
T. J. Shors, C. Lewczyk, M. Paczynski, P. R. Mathew, & J. Pickett, ...1998
;
G. E. Wood & T. J. Shors, 1998
). The authors report that these effects extend to performance on the hippocampal-dependent task of trace conditioning. The stress-induced impairment of conditioning in females was evident immediately, 24 hr and 48 hr after stress, depending on the stage of estrus. Moreover, the effect could be reactivated days later by reexposure to the stressful context. Corticosterone levels correlated with overall performance in males but not in females. Unlike the effect seen in males, adrenalectomy did not prevent the stress-induced effect on conditioning in females. These data indicate that exposure to the same experience can have opposite effects on learning in males versus females and that these opposing effects are mediated by differing hormonal systems.
A new method for the synthesis of 2-(N-phenylamino)benzoic acids is presented, with 2-fluorobenzoic acids and anilines as starting materials. Several experimental conditions as well as the factors ...influencing the outcome of the reaction are described.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
6.
The modulation of Pavlovian memory Shors, Tracey J; Beylin, Anna V; Wood, Gwendolyn E ...
Behavioural brain research,
06/2000, Letnik:
110, Številka:
1
Journal Article
Recenzirano
Exposure to stressful experiences as well as sex differences in the brain are known to influence the acquisition of new memories. This review focuses on acquisition of two types of Pavlovian learning ...paradigms: hippocampal-independent delay conditioning and hippocampal-dependent trace conditioning and their modulation by exposure to stressful experience and sex differences in the brain. We concentrate on two sets of findings: the first is that exposure to an acute stressful experience enhances Pavlovian conditioning in the male rat, while exposure to the very same experience dramatically impairs conditioning in female rat. The sexually-opposed effects of stress on conditioning are mediated by differing hormonal substrates (adrenal versus ovarian steroids) and possibly by differing anatomical and biochemical pathways. The second set of findings is that training with hippocampal-dependent trace conditioning enhances the survival of newly generated neurons in the adult hippocampal formation. The same amount of training with hippocampal-independent delay conditioning does not affect their survival. In addition, females acquire the trace task faster than males and generate more new neurons. As with the stress effects on learning, these sex effects are influenced by hormonal status. It is our contention that identifying the hormonal and neuronal processes that modulate associative memory formation will provide insight into the processes of memory formation itself.
Model of vectorlike technicolor Beylin, V. A.; Vereshkov, G. M.; Kuksa, V. I.
Physics of particles and nuclei letters,
2016/1, Letnik:
13, Številka:
1
Journal Article
Recenzirano
The authors consider the mechanism of formation of techniquark states which have a vectorlike interaction with the standard bosons. It is shown that the simplest variant of the vectorlike technicolor ...does not contradict to the new physics restrictions. It is suggested that the technibaryon scalar states are regarded as dark matter candidates.
We analyze a connection between the neutralino mass sign, parity and structure of the neutralino–boson interaction. Correct calculation of spin-dependent and spin-independent contributions to ...neutralino–nuclear scattering should consider this connection. A convenient diagonalization procedure, based on the exponential parametrization of unitary matrix, is suggested.
5-Amino-3-beta-D-ribofuranosylpyrazolo3,4-e1,3oxazin-7-o ne has been synthesized via cyclization of the appropriately protected pyrazofurin derivatives and subsequent transformations of the ...heterocyclic moiety. This guanosine analogue was marginally cytotoxic to L1210 cells in vitro. The xanthosine analogue 3-beta-D-ribofuranosylpyrazolo3,4-e1,3oxazine-5,7-dione was also synthesized, and was found to be highly cytotoxic. It appeared to act as a prodrug of pyrazofurin.
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