1,721,078 research outputs found
Lights and shadows of electrophile signaling: Focus on the Nrf2-Keap1 pathway
No full textTargeted covalent modification is assuming consolidated importance in drug discovery. In this context, the electrophilic tuning of redox-dependent cell signaling is attracting major interest, as it opens prospect for treating numerous pathologic conditions. Herein, we discuss the rationale and the issues of electrophile-based approaches, focusing on the transcriptional Nrf2-Keap1 pathway as a test case. We also highlight relevant medicinal chemistry strategies researchers have devised to meet the ambitious goal, dwelling on the investigational and therapeutic potential of modulating redox-signaling networks through regulatory cysteine switches
I maltrattamenti intrafamiliari ed extrafamiliari dell'anziano: come riconoscerli e prevenirli
No full textIl fenomeno del maltrattamento sulla persona anziana con definizione, statistiche e caratteristiche. Il ruolo del medico legale nel riconoscimento dei segni di maltrattamento e nella prevenzione
Design, synthesis and biological activity of some tetraamines related to methoctramine and 4-DAMP
No full textThree novel tetraamines (1-3) related to methoctramine were designed, and their biological profiles at muscarinic receptor subtypes were assessed by binding assays. It turned out that the constrained analogue spirotramine (3, FC 15-94) of 4-DAMP has an affinity profile better than that of pirenzepine owing to a high affinity for muscarinic M(1) receptors and a significantly lower affinity for the M(2), M(3) and M(4) subtypes
Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease
Full text linkMemantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors
Further investigation on methoctramine-related tetraamines: Effects of terminal N-substitution and of chain length separating the four nitrogens on M2 muscarinic receptor blocking activity
No full textA series of tetraamines related to methoctramine (1) was synthesized and evaluated for its blocking activity on M2 and M3 muscarinic receptors of guinea pip left atria and ileum, respectively. Thus, tetraamines 2-7 were synthesized to evaluate the effect on affinity of replacing the 2-methoxybenzyl moiety of methoctramine by a phenethyl-type substituent. Furthermore, tetraamines 8 and 9 were investigated to analyze the effect on affinity of the chain length separating the inner nitrogens and the inner from outer nitrogens while keeping the total distance between the two outer nitrogens equal to that of methoctramine. It turned out that all the tetraamines investigated, although showing a significant affinity, were less active than methoctramine at M2 muscarinic receptors. The underlying drug-receptor interaction mechanisms are discussed
Understanding the pharmacogenetics of selective serotonin reuptake inhibitors
No full textThe genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues
Search for α1-adrenoceptor subtypes selective antagonists: Design, synthesis and biological activity of cystazosin, an α(1D)-adrenoceptor antagonist
No full textTwo novel quinazolines (2 and 3) related to both prazosin and its open analogue 1 were synthesized, and their biological profile at α1- adrenoceptor subtypes was assessed by functional assays in rat isolated tissues, namely prostatic vas deferens (α(1A)), spleen (α(1B)) and aorta (α(1D)). Furthermore, the binding profile of 3 was assessed at native α2 and D2 receptors, and cloned human 5-HT(1A) receptors, in comparison to prazosin, (+)-cyclazosin, 1 and BMY 7383. It turned out that the cystamine- bearing quinazoline 3 (cystazosin) has a reversed affinity profile relative to (+)-cyclazosin owing to a higher affinity for α(1D)-adrenoceptors and a significantly lower affinity for the α(1A) and α(1B) subtypes. Furthermore, in comparison to BMY 7378, cystazosin (3) displays a much better specificity profile since it has lower affinity for D2 and 5-HT(1A) receptors
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