Agentes multidiana derivados de melatonina y resveratrol para la enfermedad de Alzheimer y ligandos fotomodulables del receptor nicotínico muscular

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 11-10-2019Alzheimer´s disease (AD) is a complex multifactorial illness with no effective treatment, characterized by irreversible global cognitive impairment. As only symptomatic treatment sare available with drugs acting at one single target, exploration of molecules active indifferent pathological targets is required. In this chapter, our objective was to develop new families of multitarget directed ligands (MTDLs) focused on some pathological pathways underlying AD, namely, oxidative stress and neuro inflammation. Thus, we design melatonin- and resveratrol-based MTDLs looking for activity in melatonin receptors (MT1-3Rs), monoaminoxidases (MAO-A/B), lipoxygenase-5 (LOX-5), and nuclear factor erythroid 2-related factor 2 (Nrf2). Considering the neuroprotective and neurogenic properties found in melatonin and resveratrol, we reasonably expected these activities in our MTDLs...La enfermedad de Alzheimer (EA) es un desorden multifactorial sin cura efectiva,caracterizada por un deterioro cognitivo global. Los tratamientos disponibles son sólo sintomáticos con fármacos que actúan sobre una sola diana, siendo necesarias moléculas activas por diferentes vías. En este capítulo, nuestro objetivo es desarrollar nuevas familias de ligandos multidiana (MTDL) enfocados hacia vías patológicas de la EA, concretamente, el estrés oxidativo y neuroinflamación. Así, desarrollamos MTDLs basados en melatoninay resveratrol buscando actividad en receptores de melatonina (MT1-3Rs), monoaminooxidasas (MAO-A/B), lipoxigenasa-5 (LOX-5) y el factor nuclear (erythroid-derived 2)-like 2 (Nrf2). Considerando las propiedades neuroprotectoras y neurogénicas de la melatonina y el resveratrol, esperamos razonablemente estas actividades en nuestros MTDLs...Fac. de Ciencias QuímicasTRUEunpu

New cinnamic – N-benzylpiperidine and cinnamic – N,N-dibenzyl(N-methyl)amine hybrids as Alzheimer-directed multitarget drugs with antioxidant, cholinergic, neuroprotective and neurogenic properties

Here we describe new families of multi-target directed ligands obtained by linking antioxidant cinnamic-related structures with N-benzylpiperidine (NBP) or N,N-dibenzyl(N-methyl)amine (DBMA) fragments. Resulting hybrids, in addition to their antioxidant and neuroprotective properties against mitochondrial oxidative stress, are active at relevant molecular targets in Alzheimer’s disease, such as cholinesterases (hAChE and hBuChE) and monoamine oxidases (hMAO-A and hMAO-B). Hybrids derived from umbellic – NBP (8), caffeic – NBP (9), and ferulic – DBMA (12) displayed balanced biological profiles, with IC50s in the low-micromolar and submicromolar range for hChEs and hMAOs, and an antioxidant potency comparable to vitamin E. Moreover, the caffeic – NBP hybrid 9 is able to improve the differentiation of adult SGZ-derived neural stem cells into a neuronal phenotype in vitro.Financial support from the Spanish Ministry of Economy and Competitiveness (MINECO, grants SAF2012-31035 and SAF2015-64948-C2-1-R to MIRF; grant SAF2014-52940-R to APC) partially financed by FEDER funds, and Consejo Superior de Investigaciones Científicas (CSIC, grant PIE-201580E109) is gratefully acknowledged. ME thanks COLCIENCIAS (Colombia) for a Ph.D. fellowship.Peer reviewe

Neurogenic inducers based on the chromone scaffold, a new family of multitarget directed ligands for Alzheimer's disease

Resumen del trabajo presentado a la XXXVIII Reunión Anual del Grupo Español de Neurotransmisión y Neuroprotección (GENN), celebrada en Almagro (Ciudad Real) del 13 al 15 de diciembre de 2017.The highly complex pathophysiology of Alzheimer's disease (AD) and other neurodegenerative illnesses have led to replace the traditional one-drug - one-target by the multi-target-directed ligands (MTDLs) paradigm, in which a single molecule is designed to be active against several pharmacological targets. Continuing with our interest in neuroprotective and neurogenic compounds, in this work we describe a new family of donepezil flavonoid hybrids exhibiting nanomolar affinities for the sigma-1 receptor and a combined inhibition of key enzymes in AD, such as 5-lipoxygenase, acetylcholinesterase, and monoaminoxidases. In general, they scavenge free radical species and are predicted to be brain-permeable. In phenotypic assays, new hybrids protect neuronal cells against mitochondrial oxidative stress and promote maturation of neural stem cells into a neuronal phenotype. Therefore, new donepezil - flavonoid hybrids could contribute to the protection and even, the reparation of neuronal tissues, of great therapeutic interest in AD and neurodegenerative diseases.Spanish Ministry of Economy and Competitiveness MINECO (grant SAF2015-64948-C2-1-R) and Spanish National Research Council CSIC (grant PIE-201580E109).Peer Reviewe

New flavonoid \u2013 N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer\ub4s disease endowed with neurogenic properties

The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid \u2013 DBMA hybrids (1\u201313) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer\u2019s disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), \u3b2-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (\u3c31R/\u3c32R). After a funnel-type screening, 6,7-dimethoxychromone \u2013 DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and \u3c31R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration

Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties

New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MT1R and MT2R, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and coplanarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MT1R and MT2R, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavoursThe authors gratefully acknowledge the following financial supports: Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grants RTI2018-093955-B-C21 and SAF2015-64948-C2-1-R to M.I.R.-F.; RTI2018-095793-B-I00 to M.G.L., SAF2015-64629-C2- 2-R to F.G.), General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827 e NRF24ADCM), Health Institute Carlos III (Miguel Servet II ProgramCP16/00014 and grant PI17/01700 to R.L.). CH-A and P.M. thank their PhD fellowships from Spanish Ministry of Education (MEC, PhD grant FPU16/01704 and mobility grant FPUEST17/00233 to CH-A and FPU13/03737 to P.M.)

Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades

By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multi- target-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1- yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 μM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 μM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.The authors gratefully acknowledge the following financial supports: the Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; European Regional Development Funds (grants RTI2018-093955-B-C21, SAF2015-64948-C2-1-R, and PID2021-122650OB-I00 to M.I.R.-F.; RTI2018-095793-B-I00 to M.G.L.); Spanish Na- tional Research Council (CSIC grants, PIE-202080E118 to M.I.R.-F. and PIE-202080I026 to R.L.); Health Institute Carlos III (grant PI17/01700 to R.L.); and General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827- NRF24ADCM). They thank the Ministry of Education of Spain for the following fellowships: FPU16/01704 and mobility grant FPUEST17/00233 (to C.H.-A.), FPU15/ 03269 (to C.F.-M.), FPU18/00630 (to E.d.S.), and FPU13/ 03737 (to P.M.). R.L. and M.G.L. also thank “Fundación Teófilo Hernando” for its continued support. The Spanish Medicinal Chemistry Society (SEQT) awarded the “Lilly Prize for Young Researchers” to this work, presented by C.H.-A. at the XIX SEQT Awards.Peer reviewe

Structure-activity relationship of potent photo-switchable neuromuscular inhibitors

Muscular nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels located in the plasma membrane of the post-junctional motor endplate in skeletal muscles. These receptors are responsible for triggering the electrical signal that leads to muscle contraction. Here, we have developed a family of photoisomerizable nAChR inhibitors, using the azobenzene scaffold. Biochemical assays showed that all these novel compounds have higher affinity for muscular nAChR (up to 60-fold) than for either ¿7 or ¿4ß2 nAChRs. Thus, we proceeded to characterize the action of these compounds on the activity of the embryonic muscular nAChR expressed in Xenopus oocytes. To do so, we recorded currents evoked by acetylcholine, using the Two-Electrode Voltage-Clamp technique. In doing so, we observed that all but one of the compounds were effective inhibitors of the receptor¿s activity. As reported elsewhere, azobenzene-based molecules can be as either cis- or trans-isomers, displaying remarkable difference in their pharmacology. To test whether the isomer had different inhibitory activity, we proceeded to irradiate the drugs with either near UV (335-365 nm) or blue light (400-450 nm) while recording currents. In all cases, we observed that the trans-isomers were the most potent form of these molecules. The main difference among the compounds of this family is the ¿molecular volume¿ of the functional group. The molecules were effective inhibitors of the receptor with nano- to micromolar activity, decreasing their potency as their size decrease. In fact, the trans-isomer of the smallest derivative reverting its behavior, acting as an agonist drug, with the cis-isomer being unable to activate the channels. In terms structure-activity relationship (SAR) parameters, these observations led us to infer the that decreasing the bulkiness of the molecule is a critical determinant of the character and potency of these novel azobenzene-based inhibitors.MINECO (SAF2015-64948-C2-1-R; CHA: FPU16/01704; FPUEST17/00233), CSIC (PIE201580E109), Nutting Foundation Grant (CAVG)

Recent Advances in Neurogenic Small Molecules as Innovative Treatments for Neurodegenerative Diseases

The central nervous system of adult mammals has long been considered as a complex static structure unable to undergo any regenerative process to refurbish its dead nodes. This dogma was challenged by Altman in the 1960s and neuron self-renewal has been demonstrated ever since in many species, including humans. Aging, neurodegenerative, and some mental diseases are associated with an exponential decrease in brain neurogenesis. Therefore, the controlled pharmacological stimulation of the endogenous neural stem cells (NSCs) niches might counteract the neuronal loss in Alzheimer’s disease (AD) and other pathologies, opening an exciting new therapeutic avenue. In the last years, druggable molecular targets and signalling pathways involved in neurogenic processes have been identified, and as a consequence, different drug types have been developed and tested in neuronal plasticity. This review focuses on recent advances in neurogenic agents acting at serotonin and/or melatonin systems, Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase (NAMPT) and nuclear erythroid 2-related factor (Nrf2)