RESUMEN
In recent years, the multi-target-directed ligand concept has been used to design a variety of molecules hitting different biological targets for Alzheimer's disease. We have sought to combine, in the same molecule, the neuroprotective action of N-methyl-D-aspartate receptor antagonism with the symptomatic relief offered by cholinergic activity through acetylcholinesterase inhibition. This strategy could potentially maintain the positive outcomes of memantine-acetylcholinesterase inhibitor combinations, but with the benefits of a single molecule therapy. Herein, we discuss selected examples of multifunctional compounds, which we rationally designed to simultaneously modulate these targets. We also examine the intertwined relationship between acetylcholinesterase, N-methyl-D-aspartate receptors, and other active players in the neurotoxic cascade.
Asunto(s)
Acetilcolinesterasa/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Enfermedad de Alzheimer/enzimología , HumanosRESUMEN
Redox impairment is a prominent feature of Alzheimer's disease (AD). It has led to the "oxidative stress hypothesis", which proposes antioxidants as beneficial therapeutic tools in AD treatment. To date, a wide variety of antioxidants have been examined as neuroprotectants. However, success has been elusive in clinical trials. Several factors have contributed to this failure, including the complexity of the redox system in vivo. Potentially critical aspects include the fine-tuned equilibrium between antioxidant defenses and free radical production, the lack of specific antioxidant target(s), and the inherent difficulty in delivering antioxidants where they are needed. Herein, we highlight significant progress in the field. Future directions of antioxidant research are also presented.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , HumanosRESUMEN
Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Galantamina/farmacología , Memantina/farmacología , Neuroblastoma/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Acetilcolinesterasa/química , Enfermedad de Alzheimer/prevención & control , Animales , Proliferación Celular/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Simulación por Computador , Combinación de Medicamentos , Diseño de Fármacos , Estudios de Factibilidad , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Multitarget agents directed at selected molecular targets involved in the pathogenic cascade of Alzheimer's disease (AD) have been increasingly sought after in recent years, with the aim of achieving enhanced therapeutic efficiency with respect to single-target drugs and drug candidates. At the same time, much attention has been devoted to identifying high quality pharmacological tools to help explore the molecular mechanisms underlying AD without being exposed to physicochemical challenges. Herein, we discuss several examples of both types of compounds, taken from our own research and derived from the leads memoquin, lipocrine and bis(7)tacrine.
Asunto(s)
Alcanos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Etilaminas/farmacología , Tacrina/análogos & derivados , Ácido Tióctico/análogos & derivados , Acetilcolinesterasa/metabolismo , Alcanos/química , Enfermedad de Alzheimer/enzimología , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/química , Etilaminas/química , Humanos , Ligandos , Tacrina/química , Tacrina/farmacología , Ácido Tióctico/química , Ácido Tióctico/farmacologíaRESUMEN
Eight monomeric congeners, related to the multitarget lead candidate memoquin, were prepared and evaluated at multiple targets to determine their profile against Alzheimer's disease. 2-4 bind to AChE with similar low nanomolar affinities and function as effective inhibitors of amyloid aggregation. The most potent monovalent ligand 2 also inhibits BACE-1 in vitro and APP metabolism in primary chicken telencephalic neurons.
Asunto(s)
Alcanos/síntesis química , Etilaminas/síntesis química , Acetilcolinesterasa/química , Alcanos/química , Alcanos/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/química , Dominio Catalítico , Supervivencia Celular/efectos de los fármacos , Pollos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Etilaminas/química , Etilaminas/farmacología , Humanos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Conformación Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Unión Proteica , Relación Estructura-ActividadRESUMEN
Lipoic acid (LA) is a natural antioxidant. Its structure was previously combined with that of the acetylcholinesterase inhibitor tacrine to give lipocrine (1), a lead compound multitargeted against Alzheimer's disease (AD). Herein, we further explore LA as a privileged structure for developing multimodal compounds to investigate AD. First, we studied the effect of LA chirality by evaluating the cholinesterase profile of 1's enantiomers. Then, a new series of LA hybrids was designed and synthesized by combining racemic LA with motifs of other known anticholinesterase agents (rivastigmine and memoquin). This afforded 4, which represents a step forward in the search for balanced anticholinesterase and antioxidant capacities.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Ácido Tióctico/química , Ácido Tióctico/farmacología , Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides/química , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Butirilcolinesterasa/metabolismo , Línea Celular , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Humanos , Ligandos , Fragmentos de Péptidos/química , Multimerización de Proteína/efectos de los fármacos , Estructura Secundaria de Proteína , Ácido Tióctico/síntesis química , Ácido Tióctico/uso terapéuticoRESUMEN
Memoquin (1) is a lead compound multitargeted against Alzheimer's disease (AD). It is an AChE inhibitor, free-radical scavenger, and inhibitor of amyloid-ß (Aß) aggregation. A new series of 1 derivatives was designed and synthesized by linking its 2,5-diamino-benzoquinone core with motifs that are present in the structure of known amyloid binding agents like curcumin, the benzofuran derivative SKF64346, or the benzothiazole bearing compounds KHG21834 and BTA-1. The weaker AChE inhibitory potencies and the concomitant nearly equipotent anti-amyloid activities of the new compounds with respect to 1 resulted in a more balanced biological profile against both targets. Selected compounds turned out to be effective Aß aggregation inhibitors in a cell-based assay. By properly combining two or more distinct pharmacological properties in a molecule, we can achieve greater effectiveness compared to single-targeted drugs for investigating AD.
Asunto(s)
Alcanos/química , Amiloide/antagonistas & inhibidores , Inhibidores de la Colinesterasa/síntesis química , Sistemas de Liberación de Medicamentos , Descubrimiento de Drogas , Etilaminas/química , Alcanos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Amiloide/genética , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/genética , Células Cultivadas , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores Enzimáticos/farmacología , Etilaminas/farmacología , Humanos , Concentración 50 Inhibidora , Estructura MolecularRESUMEN
Tamsulosin (-)-1 is the most utilized α(1)-adrenoceptor antagonist in the benign prostatic hyperplasia therapy owing to its uroselective antagonism and capability in relieving both obstructive and irritative lower urinary tract symptoms. Here we report the synthesis and pharmacological study of the homochiral (-)-1 analogues (-)-2-(-)-5, bearing definite modifications in the 2-substituted phenoxyethylamino group in order to evaluate their influence on the affinity profile for α(1)-adrenoceptor subtypes. The benzyl analogue (-)-3, displaying a preferential antagonist profile for α1A-than α1D-and α1B-adrenoceptors, and a 12-fold higher potency at α1A-adrenoceptors with respect to the α1B subtype, may have improved uroselectivity compared to (-)-1.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/síntesis química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Receptores Adrenérgicos alfa 1/metabolismo , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/química , Animales , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/química , TamsulosinaRESUMEN
Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation. Notably, the insertion of a polyamine function into the curcumin-like moiety allowed an efficient intracellular uptake and mitochondria targeting. It also resulted in a significant decrease in the cytotoxicity effects. 2-5 are therefore promising molecules for neuroprotectant lead discovery.
Asunto(s)
Antioxidantes/síntesis química , Curcumina/análogos & derivados , Curcumina/síntesis química , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Poliaminas/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antioxidantes/farmacología , Bovinos , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Curcumina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Activación Enzimática , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Hemo-Oxigenasa 1/metabolismo , Humanos , Técnicas In Vitro , Ratones , Mitocondrias/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Poliaminas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estereoisomerismo , Relación Estructura-ActividadAsunto(s)
Acetilcolinesterasa/química , Amiloide/química , Inhibidores de la Colinesterasa/química , Tacrina/análogos & derivados , Acetilcolinesterasa/metabolismo , Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Simulación por Computador , Diseño de Fármacos , Humanos , Ligandos , Tacrina/síntesis química , Tacrina/química , Tacrina/farmacologíaRESUMEN
The binding of polyamines to a variety of receptors and other defined recognition sites has been widely reported. It is well-known that polyamines interact with aspartate, glutamate, and aromatic residues of a given receptor and/or enzyme mainly through the formation of ion bonds, since at physiological pH, protonation of amino groups is nearly complete. From this, the hypothesis arises that a polyamine may be a universal template able to recognize different receptor systems. This hypothesis suggests that both affinity and selectivity may be fine-tuned by inserting appropriate substituents onto the amine functions and by varying the methylene chain lengths between them on the polyamine backbone. In this paper, we detail several application of this design strategy aimed at discovering potent and selective polyamines able to bind neurotransmitter receptors and enzymes, such as muscarinic receptor subtypes, muscle-type nicotinic receptors and acethylcholinesterase.
Asunto(s)
Poliaminas/química , Poliaminas/metabolismo , Animales , Enzimas/química , Enzimas/metabolismo , Humanos , Cinética , Estructura Molecular , Poliaminas/síntesis química , Unión Proteica , Receptores de Neurotransmisores/química , Receptores de Neurotransmisores/metabolismoRESUMEN
Naphthalimmide (NI) and 1,4,5,8-naphthalentetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity. NDI derivatives 1-9 were more cytotoxic than the corresponding NI derivatives 10-18. The molecular mechanisms of 1 and 2 were investigated in comparison to mitonafide. They interacted with DNA, were not topoisomerase IIalpha poisons, triggered caspase activation, caused p53 protein accumulation, and down-regulated AKT survival. Furthermore, 1 and 2 caused a decrease of ERK1/2 and, unlike mitonafide, inhibited ERKs phosphorylation.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Imidas/química , Imidas/farmacología , Naftalenos/química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/metabolismo , Diseño de Fármacos , Humanos , Imidas/metabolismo , Imidas/toxicidad , Inhibidores de TopoisomerasaRESUMEN
Novel multitargeted antioxidants 3-6 were designed by combining the antioxidant features, namely, a benzoquinone fragment and a lipoyl function, of two multifunctional lead candidates. They were then evaluated to determine their profile against Alzheimer's disease. They showed antioxidant activity, improved following enzymatic reduction, in mitochondria and T67 cell line. They also displayed a balanced inhibitory profile against amyloid-beta aggregation and acetylcholinesterase, emerging as promising molecules for neuroprotectant lead discovery.
Asunto(s)
Alcanos/química , Antioxidantes/química , Antioxidantes/farmacología , Etilaminas/química , Ácido Tióctico/química , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/metabolismo , Antioxidantes/metabolismo , Línea Celular Tumoral , Diseño de Fármacos , Transporte de Electrón , Humanos , Ligandos , Unión Proteica/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Partículas Submitocóndricas/efectos de los fármacos , Partículas Submitocóndricas/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/metabolismoRESUMEN
Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Antineoplásicos/síntesis química , Doxazosina/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/farmacología , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Células CHO , Línea Celular Tumoral , Cricetinae , Cricetulus , Humanos , Masculino , Ratones , Neoplasias de la Próstata/patología , Ratas , Relación Estructura-ActividadRESUMEN
Methoctramine and its analogues are polymethylene tetramines that selectively bind to a variety of receptor sites. Although these compounds are widely used as pharmacological tools for receptor characterization, the toxicological properties of these polyamine-based structures are largely unknown. We have evaluated the cytotoxic effects of methoctramine and related symmetrical analogues differing in polymethylene chain length between the inner nitrogens against a panel of cell lines. Methoctramine caused cell death only at high micromolar concentrations, whereas its pharmacological action is exerted at nanomolar level. Increasing the spacing between the inner nitrogen atoms resulted in a significative increase in cytotoxicity. In particular, an elevated cytotoxicity is associated to a methylene chain length of 12 units dividing the inner amine functions (compound 5). H9c2 cardiomyoblasts were the most sensitive cells, followed by SH-SY5Y neuroblastoma, whereas HL60 leukaemia cells were much more resistant. Methoctramine and related compounds down-regulated ornithine decarboxylase, the first enzyme of polyamine biosynthesis even at non-toxic concentration. Further, methoctramine and compound 5 caused a limited up-regulation of spermine/spermidine N-acetyltransferase, suggesting that interference in polyamine metabolism is not a primary mechanism of toxicity. Methoctramine and its analogues bound to DNA with a higher affinity than spermine, but the correlation with their toxic effect was poor. The highly toxic compound 5 killed the cells in the absence of caspase activation and caused an increase in p53 expression and ERK1/2 phosphorylation. Compound 5 was directly oxidized by cell homogenates producing hydrogen peroxide and its toxic effect was partially subdued by the inhibition of its uptake, by the NMDA ligand MK-801, and by the antioxidant N-acetylcysteine, suggesting that compound 5 can act at different cellular levels and lead to oxidative stress.
Asunto(s)
Muerte Celular/efectos de los fármacos , Diaminas/farmacología , Poliaminas/farmacología , Western Blotting , Línea Celular Tumoral , Diaminas/química , Humanos , Poliaminas/químicaRESUMEN
The present article expands on the study of structure-activity relationships of the novel class of quinone-bearing polyamines, as multi-target-directed ligands against Alzheimer's disease. Namely, the effect of inserting a methyl substituent at the alpha position of the terminal benzyl amine moieties of lead candidate 1 (memoquin) was evaluated at the multiple targets involved in the multifunctional mechanism of action. The RR stereoisomer 2 resulted more effective than 1 in reverting two important effects mediated by acetylcholinesterase (AChE), that is, acetylcholine hydrolysis and AChE-induced amyloid-beta aggregation.
Asunto(s)
Alcanos/síntesis química , Etilaminas/síntesis química , Acetilcolinesterasa/química , Alcanos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Aminas/química , Péptidos beta-Amiloides/química , Animales , Relación Dosis-Respuesta a Droga , Etilaminas/farmacología , Humanos , Hidrólisis , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Poliaminas/química , Quinonas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In this work, we review and comment upon the challenges and the 'quo vadis' in Alzheimer's disease drug discovery at the beginning of the new millennium. We emphasize recent approaches that, moving on from a target-centric approach, have produced innovative molecular probes or drug candidates. In particular, the discovery of endosome-targeted BACE1 inhibitors and mitochondria-targeted antioxidants represents a significant advance in Alzheimer's research and therapy. The case study of the development of rasagiline provides an excellent example to support the validity of the multitarget-designed ligand approach to the search for effective medicines for combating Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Humanos , Indanos/química , Compuestos Organofosforados/química , Ubiquinona/análogos & derivados , Ubiquinona/químicaRESUMEN
The photostability properties of memoquin, a multifunctional compound in preclinical development for the treatment of Alzheimer's disease (AD) were investigated in solutions exposed to radiations, using a xenon arc lamp to simulate the natural sunlight. Reversed phase liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry (LC-UV/DAD-ESI-MS/MS) was applied to follow the photodegradation and disappearance of memoquin after irradiation. Under optimized chromatographic conditions, memoquin was separated with high resolution from the photoproducts formed in the photoexposed solutions. The results showed that memoquin is more stable at physiological and acid pHs, while it has a slow degradation pattern at more drastic conditions such as basic pH (t(1/2)=389 min) and in methanolic solutions (t(1/2)=465 min). In the irradiated solutions the appearance of photoproducts with lower retention times and molecular weight than memoquin was observed, thus indicating that some fragments were lost from its structure. The photodegradation products were characterized by LC-ESI-MS/MS and LC-UV/DAD analysis. The photoreactive centers were found on the amino groups of the side chains while the 1,4-benzoquinone functionality was maintained. Conversely, memoquin was found to be stable in the dark. These results suggest that, with appropriate handling and storage, memoquin's activity is not impaired.
Asunto(s)
Alcanos/química , Enfermedad de Alzheimer/tratamiento farmacológico , Etilaminas/química , Luz , Alcanos/uso terapéutico , Cromatografía Liquida , Estabilidad de Medicamentos , Etilaminas/uso terapéutico , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta , Espectrometría de Masas en TándemRESUMEN
Alzheimer's disease is currently thought to be a complex, multifactorial syndrome, unlikely to arise from a single causal factor; instead, a number of related biological alterations are thought to contribute to its pathogenesis. This may explain why the currently available drugs, developed according to the classic drug discovery paradigm of "one-molecule-one-target," have turned out to be palliative. In light of this, drug combinations that can act at different levels of the neurotoxic cascade offer new avenues toward curing Alzheimer's and other neurodegenerative diseases. In parallel, a new strategy is emerging-that of developing a single chemical entity able to modulate multiple targets simultaneously. This has led to a new paradigm in medicinal chemistry, the "multi-target-directed ligand" design strategy, which has already been successfully exploited at both academic and industrial levels. As a case study, we report here on memoquin, a new molecule developed following this strategy. The in vitro and in vivo biological profile of memoquin demonstrates the suitability of the new strategy for obtaining innovative drug candidates for the treatment of neurodegenerative diseases.