Editorial: Antimicrobial Resistance as a Global Public Health Problem: How Can We Address It?

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Search for selective antagonists at alpha1-adrenoreceptors: neutral or negative antagonism?

In this article the use of competitive antagonists as tools in receptor characterization and classification is discussed. It is pointed out that caution is required in receptor characterization because negative antagonism (inverse agonism) rather than neutral antagonism could play a relevant role. This implies that antagonists should be evaluated not only with regard to their affinity, but also with regard to their ability to affect the equilibrium between the two receptor states, namely active and inactive states. Since affinity and efficacy of a negative antagonist are system dependent the use of negative antagonists as competitive antagonists in receptor characterization may give rise to false differences in receptor subtypes. Finally, this article summarizes recent developments in the design of new alpha 1-adrenoreceptor antagonists which are structurally related to prazosin or WB 4101

Inhibition of Acetylcholinesterase, Beta-Amyloid Aggregation, and NMDA Receptors in Alzheimer's Disease: A Promising Direction for the Multi-target-Directed Ligands Gold Rush

Alzheimer\u2019s disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced beta-aggregation and display antioxidant properties, emerging as lead candidates for treating AD

Tetraamines as lead compounds for the design of neurotransmitter receptor ligands:Focus on α-adrenergic and muscarinic receptors recognition

The concept that polyamines may represent a passe-partout (Master key) for G-protein-coupled receptors recognition is illustrated. Using a linear tetraamine as the focus, appropriate structural modifications have allowed to obtain novel tetraamines displaying selectivity for different receptor systems. It is shown that tetraamines have receptor subtype selectivity since they are site-directed, owing to different chain lengths separating the protonable nitrogens and to the presence of those peculiar structural elements which make them able of discriminating at the binding stage. © 1996 Elsevier B.V. All rights reserved

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates