A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel ...compounds (3–9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 ± 1.1 nM) and MAO-B (IC50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 ± 0.01 μM) and BuChE (IC50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer’s disease therapy.
Metal exposure is associated with several toxic effects; herein, we review the toxicity mechanisms of cadmium, mercury, arsenic, lead, aluminum, chromium, iron, copper, nickel, cobalt, vanadium, and ...molybdenum as these processes relate to free radical generation. Free radicals can be generated in cells due to a wide variety of exogenous and endogenous processes, causing modifications in DNA bases, enhancing lipid peroxidation, and altering calcium and sulfhydryl homeostasis. Melatonin, an ubiquitous and pleiotropic molecule, exerts efficient protection against oxidative stress and ameliorates oxidative/nitrosative damage by a variety of mechanisms. Also, melatonin has a chelating property which may contribute in reducing metal‐induced toxicity as we postulate here. The aim of this review was to highlight the protective role of melatonin in counteracting metal‐induced free radical generation. Understanding the physicochemical insights of melatonin related to the free radical scavenging activity and the stimulation of antioxidative enzymes is of critical importance for the development of novel therapeutic strategies against the toxic action of these metals.
Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical ...trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.
Background and Purpose
Refractory status epilepticus is a clinical emergency associated with high mortality and morbidity. Increasing evidence suggests neuroinflammation contributes to the ...development of drug‐refractoriness during status epilepticus. Here, we have determined the contribution of the ATP‐gated P2X7 receptor, previously linked to inflammation and increased hyperexcitability, to drug‐refractory status epilepticus and its therapeutic potential.
Experimental Approach
Status epilepticus was induced via a unilateral microinjection of kainic acid into the amygdala in adult mice. Severity of status epilepticus was compared in animals with overexpressing or knock‐out of the P2X7 receptor, after inflammatory priming by pre‐injection of bacterial lipopolysaccharide (LPS) and in mice treated with P2X7 receptor‐targeting and anti‐inflammatory drugs.
Key Results
Mice overexpressing P2X7 receptors were unresponsive to several anticonvulsants (lorazepam, midazolam, phenytoin and carbamazepine) during status epilepticus. P2X7 receptor expression increased in microglia during status epilepticus, at times when responses to anticonvulsants were reduced. Overexpression of P2X7 receptors induced a pro‐inflammatory phenotype in microglia during status epilepticus and the anti‐inflammatory drug minocycline restored normal responses to anticonvulsants in mice overexpressing P2X7 receptors. Pretreatment of wild‐type mice with LPS increased P2X7 receptor levels in the brain and reduced responsiveness to anticonvulsants during status epilepticus, which was overcome by either genetic deletion of P2X7 receptors or treatment with the P2X7 receptor antagonists, AFC‐5128 or ITH15004.
Conclusion and Implications
Our results demonstrate that P2X7 receptor‐induced pro‐inflammatory effects contribute to resistance to pharmacotherapy during status epilepticus. Therapies targeting P2X7 receptors could be novel adjunctive treatments for drug‐refractory status epilepticus.
Melatonin is an endogenous hormone produced by the pineal gland as well as many other tissues and organs. The natural decline in melatonin levels with ageing contributes significantly to the ...development of neurodegenerative disorders. Neurodegenerative diseases share common mechanisms of toxicity such as proteinopathy, mitochondrial dysfunction, metal dyshomeostasis, oxidative stress, neuroinflammation and an imbalance in the phosphorylation/dephosphorylation ratio. Several reports have proved the usefulness of melatonin in counteracting the events that lead to a neurodegenerative scenario. In this review, we have focused on the fact that melatonin could rectify the altered phosphorylation/dephosphorylation rate found in some neurodegenerative diseases by influencing the activity of phosphoprotein phosphatases. We analyse whether melatonin offers any protective activity towards these enzymes through a direct interaction.
Linked Articles
This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc
Tacrine was the first drug approved for the treatment of Alzheimer's disease (AD) in 1993, which was withdrawn in 2013 due to its hepatotoxicity. However, new, non-hepatotoxic tacrine derivatives ...have been constantly searched for. In this context, since 1997, we have prepared a number of diversely functionalized tacrines by changing the benzene ring present in tacrine to five- or six-membered aromatic ring cores that could present anticholinesterasic activity and additional pharmacological properties. The new compounds were designed as juxtaposed structures between tacrine and the well-known Ca2+ antagonists 1,4-dihydropyridines, with the goal of obtaining multi-target directed ligands for AD. In this account, we present our results on the PyridoTacrine (PyrTac) family of tacrine analogues, resulting from the substitution of the benzene ring by a pyridine. We highlight their pharmacological profile and review similar analogues in the literature. A first set of PyrTac showed inhibitory activity of cholinesterases (ChE) and a blocking profile of voltage-gated Ca2+ channels (VGCC). A second family with improved ChE inhibition lost VGCC blocking activity. However, the lead compound of this family (5f) presented an activating profile of the phosphatase 2A (PP2A) and showed interesting outcomes in experimental in vivo models of AD and stroke. We have identified the PyrTac ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzob 1,8naphthyridine-3-carboxylate (5f), which presents additional pharmacological properties beyond the mere cholinergic improvement. These new properties warrant attention to 5f and its further development as a new potential therapeutic agent for AD therapy.
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•Tacrine is a good scaffold to design multitarget drugs for Alzheimer's disease.•Pyridotacrines are derivatives from the replacement of the benzene-fused ring by pyridine.•Pyridotacrines avoid toxic metabolism and allow the design of multitarget compounds.•Among contributions by others, we described several families of Pyridotacrines.•Our compounds presented new biological activities of relevance for Alzheimer's disease.
Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront ...AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ± 15 nM) is associated to a 30.7 ± 8.6% inhibition of the proaggregating action of AChE on the Aβ and a moderate inhibition of Aβ self-aggregation (34.9 ± 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood−brain barrier, emerging as lead candidates for treating AD.
The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached ...clinical trials for this indication. In this work, we designed and synthesized novel blood–brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in Xenopus laevis oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound 6 (2-(6-chloro-9H-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound 6 can be considered as a first non-nucleotide purine hit for future drug optimizations.
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very ...promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (K i = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
N-Propargylamines are useful synthetic scaffolds for the synthesis of bioactive molecules, and in addition, they possess important pharmacological activities. We obtained several neuroprotective ...molecules, chiral 1,2-amino alcohols and 1,2-diamines, able to reduce by almost 70% the rotenone and oligomycin A-induced damage in SH-SY5Y cells. Furthermore, some molecules assessed also counteracted the toxicity evoked by the Ser/Thr phosphatase inhibitor okadaic acid. Before extrapolating these data to preclinical studies, we analyze the molecules through an in silico prediction system to detect carcinogenicity risk or other toxic effects. In light of these promising results, these molecules may be considered as a lead family of neuroprotective and relatively safe compounds.
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