1,721,060 research outputs found
Challenging cosmic censorship in Einstein-Maxwell-scalar theory with numerically simulated gedanken experiments
Full text linkWe perform extensive nonlinear numerical simulations of the spherical collapse of (charged) wave packets onto a charged black hole within Einstein-Maxwell theory and in Einstein-Maxwell-scalar theory featuring nonminimal couplings and a spontaneous scalarization mechanism. We confirm that black holes in full-fledged Einstein-Maxwell theory cannot be overcharged past extremality and no naked singularities form, in agreement with the cosmic censorship conjecture. We show that naked singularities do not form even in Einstein-Maxwell-scalar theory, although it is possible to form scalarized black holes with charge above the Reissner-Nordström bound. We argue that charge and mass extraction due to superradiance at the fully nonlinear level is crucial to bound the charge-to-mass ratio of the final black hole below extremality. We also discuss some "descalarization"mechanisms for scalarized black holes induced either by superradiance or by absorption of an opposite-charged wave packet; in all cases the final state after descalarization is a subextremal Reissner-Nordström black hole
An improved synthesis of solid-supported reagents (SSRs) for selective acylation of amines by microwave irradiation
No full textMicrowave-assisted acylation of a solid-supported pyrimidine linker with different acyl chlorides gave polymer-bound
4-acyloxypyrimidines, which in turn were used as SSRs for rapid and selective acylation of amines under microwave irradiatio
syntheses of 3b,4,6,7-tetrahydro-5H,9H-pyrazino(2,1-c)pyrrolo(1,2-a)(1,4)benzodiazepine, a valuable precursor of potential central nervous system agents
No full textPolycondensed heterocycles. VII. A convenient synthesis of pyrrolo[1,2-a]quinoxaline derivatives by intramolecular aromatic nucleophilic displacement
No full text4-(4-Methyl-1-piperazinyl)-7-trifluoromethylpyrrolo[1,2-a]quinoxaline (CGS 12066B) and related analogs were prepared in good overall yield through a reaction sequence involving as a key step the intramolecular substitution of aromatic fluoride or nitro groups by a carboxamide moiety. © 1991, Taylor & Francis Group, LLC. All rights reserved
The Selective CB2 Agonist COR167 Reduced Symptoms in a Mice Model of Trauma-Induced Peripheral Neuropathy through HDAC-1 Inhibition
Full text linkNeuropathic pain is a chronic disabling condition with a 7–10% of prevalence in the general population that is largely undertreated. Available analgesic therapies are poorly effective and are often accompanied by numerous side effects. Growing evidence indicates cannabinoids are a valuable treatment opportunity for neuropathic pain. The endocannabinoid system is an important regulator of pain perception through the CB1 receptors, but CB1 agonists, while largely effective, are not always satisfactory pain-relieving agents in clinics because of their serious adverse effects. Recently, several CB2 agonists have shown analgesic, anti-hyperalgesic, and anti-allodynic activity in the absence of CB1-induced psychostimulant effects, offering promise in neuropathic pain management. The aim of this study was to evaluate the anti-neuropathic activity of a novel selective CB2 agonist, COR167, in a preclinical model of peripheral neuropathy, the spared nerve injury (SNI). Oral COR167, in a dose-dependent manner, attenuated mechanical allodynia and thermal hyperalgesia after acute and repeated administration, showing the absence of tolerance induction. At anti-neuropathic doses, COR167 did not show any alteration in the locomotor behavior. SNI mice showed increased microglial levels of HDAC1 protein in the ipsilateral side of the spinal cord, along with NF-kB activation. COR167 treatment prevented the HDAC1 overexpression and the NF-kB activation and increased the levels of the anti-inflammatory cytokine IL-10 through a CB2-mediated mechanism. Oral administration of COR167 shows promising therapeutic potential in the management of neuropathic pain conditions
Parallel solution phase synthesis of 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines
No full textA simple and straightforward methodology for the parallel, solution-phase synthesis of novel 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines 9a-j has been developed. Starting from 2-methylthio-6-[2-(p-toluensulfonyloxy)ethan-1-yl]-4(3H)-pyrimidinone (6), a three-step procedure (namely, tosylate substitution by amines, base-catalyzed rearrangement, and sulfide to sulfone oxidation) using a Buchi Sincore synthesizer gave the final products in high yield after simple ethyl acetate extraction and without further purification. Interestingly, when the final oxidation step was performed on 4-arylpiperazine derivatives 8g-j, the corresponding highly polar piperazine N-oxides 9g-j were obtained, which conversely needed chromatographic purification in order to give the pure products
acidi 5-aroil-5,6-diidro-4H-pirrolo(1,2-a)(1,4)benzodiazepin-4-carbossilici: sintesi ed attività analgesica e neurocomportamentale
No full textheterocyclic system. XI. synthesis of 1H,4H-pyrazolo(4,3-b)pyrrolizine and 2H,4H-pyrazolo(4,3-b)pyrrolizine derivatives
No full textArylpiperazines with high affinity toward a1-adrenergic receptors
No full textIn the last years, α1 adrenoceptors (α1-AR) have been the subject of intense research, in part because receptor-binding studies and molecular biology have opened up new aspects of understanding but also because of the potential to find new drugs possibly acting toward pathophysiological processes where α1-AR are involved, such as benign prostatic hyperplasia (BPH) or hypertension. At present, arylpiperazines represent one of the most studied classes of molecules with affinity at α1-AR. In fact, a large amount of work has been done and reported, describing synthetic procedures, biological evaluation at both α1-AR and the corresponding subtypes, and structure-activity relationships (SARs). In this paper, a review based on a literature survey aimed at focusing on the structural properties that a compound should possess to show affinity toward α1-AR is presented. Moreover, the identification and optimization of the structural features of a hit compound derived from a pharmacophore-based database search, leading to a new class of arylpiperazinylalkyl pyridazinone derivatives with α1-AR affinity is reported
Structural flexibility of hyaluronan oligomers as probed by molecular modeling
No full textIn the last few years, molecular modeling studies have been published that are devoted to a better understanding of the structural flexibility of hyaluronan (HA). Further conformational investigations, however, are needed on this polysaccharide, such as the application of statistical methods to perform enhanced one-step conformational analyses of its subunits. Moreover, the adjustment of assisted model building and energy refinement (AMBER) force field could provide the appropriate computational tool to study the interactions of HA and its derivatives with proteins. The present paper reports a combined Monte Carlo (MC) and molecular dynamics (MD) approach applied to the conformational study of HA, using an adjusted version of AMBER force field and the generalized Born solvent-accessible surface area (GB/SA) continuum solvation model. The MC approach turned out to be extremely effective to outline a conformational survey of the disaccharides constituting HA. Complete sets of conformations of the monomers were provided for the first time, some of which had never been predicted. MD technique, integrating the MC results, correctly reproduced the unusual stiffness of HA and predicted the existence of a minor skew-boat conformation of the β-D-glucuronic moiety. The computational approach, as a whole, improved the comprehension of the dynamic behavior of HA and offered a clear causal explanation of the relative dynamics of the glycosidic linkages
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