RESUMEN

Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already shown positive properties in terms of muscle force recovery, this compound is not suitable for use as a therapeutic agent due to its insufficient potency. By means of in silico studies based on our recently presented allosteric binding pocket at the nAChR, i.e. the MB327-PAM-1 binding site, three promising MB327 analogs with a 4-aminopyridinium ion partial structure (PTM0056, PTM0062, and PTM0063) were identified. In this study, we present the synthesis and biological evaluation of a series of new analogs of the aforementioned compounds with a 4-aminopyridinium ion partial structure (PTM0064-PTM0072), as well as hydroxy-substituted analogs of MB327 (PTMD90-0012 and PTMD90-0015) designed to substitute entropically unfavorable water clusters identified during molecular dynamics simulations. The compounds were characterized in terms of their binding affinity towards the aforementioned binding site by applying the UNC0642 MS Binding Assays and in terms of their muscle force reactivation in rat diaphragm myography. More potent compounds were identified compared to MB327, as some of them showed a higher affinity towards MB327-PAM-1 and also a higher recovery of neuromuscular transmission at lower compound concentrations. To improve the treatment of organophosphate poisoning, direct targeting of nAChRs with appropriate compounds is a key step, and this study is an important contribution to this research.

Asunto(s)

Receptores Nicotínicos , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Animales , Masculino , Agentes Nerviosos/toxicidad , Ratas Wistar , Ratas , Intoxicación por Organofosfatos/tratamiento farmacológico , Diafragma/efectos de los fármacos , Diafragma/metabolismo , Relación Estructura-Actividad , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/química , Contracción Muscular/efectos de los fármacos , Unión Neuromuscular/efectos de los fármacos , Sitios de Unión

RESUMEN

Three unusual ajmaline-macroline type bisindole alkaloids, alsmaphylines A-C, together with their postulated biogenetic precursors, were isolated from the stem barks and leaves of Alstonia macrophylla via the building blocks-based molecular network (BBMN) strategy. Alsmaphyline A represents a rare ajmaline-macroline type bisindole alkaloid with an S-shape polycyclic ring system. Alsmaphylines B and C are two novel ajmaline-macroline type bisindole alkaloids with N-1-C-21' linkages, and the former possesses an unconventional stacked conformation due to the presence of intramolecular noncovalent interactions. The chemical structures including absolute configurations of alsmaphylines A-C were established by comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray crystallography. In addition, a plausible biosynthetic pathway of these bisindole alkaloids as well as their ability to promote the protein synthesis on HT22 cells were discussed.

Asunto(s)

Alcaloides , Alstonia , Oxindoles , Alstonia/química , Ajmalina , Alcaloides Indólicos/química , Estructura Molecular , Alcaloides/química

RESUMEN

In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA-H) and salts of sodium (-Na), calcium (-Ca), ammonium (-NH4 ), triethylammonium (-TEA), tris(hydroxymethyl)aminomethane (-Tris), benethamine (-Bnet), and benzathine (-BZ) were prepared. Their solid-state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2 O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X-ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA-BZ featured the lowest aqueous solubility and hygroscopicity, with 50 µg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X-ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP - conformation at the phosphorus atom.

Asunto(s)

Cristalografía por Rayos X , Difracción de Rayos X , Solubilidad , Cristalización , Conformación Molecular

RESUMEN

Epidermal growth factor receptor (EGFR) is a potential target with disease modifying benefits against Alzheimer's disease (AD). Repurposing of FDA approved drugs against EGFR have shown beneficial effect against AD but are confined to quinazoline, quinoline and aminopyrimidines. Futuristically, the possibility of acquiring drug resistance mutation as seen in the case of cancer could also hamper AD treatment. To identify novel chemical scaffolds, we rooted on phytochemicals identified from plants such as Acorus calamus, Bacopa monnieri, Convolvulus pluricaulis, Tinospora cordifloia, and Withania somnifera that have well-established records in the treatment of brain disorders. The rationale was to mimic the biosynthetic metabolite extension process observed in the plants for synthesizing new phytochemical derivates. Thus, novel compounds were designed computationally by fragment-based method followed by extensive in silico analysis to pick potential phytochemical derivates. PCD1, 8 and 10 were predicted to have better blood brain barrier permeability. ADMET and SoM analysis suggested that these PCDs exhibited druglike properties. Further simulation studies showed that PCD1 and PCD8 stably interact with EGFR and have the potential to be used even in cases of drug-resistance mutations. With further experimental evidence, these PCDs could be leveraged as potential inhibitors of EGFR.

Asunto(s)

Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Extractos Vegetales/química , Quinazolinas/química , Fitoquímicos/uso terapéutico , Receptores ErbB , Simulación del Acoplamiento Molecular

RESUMEN

We synthesized a family of neuromuscular blocking agents (NMB) based on decamethonium, but containing a carborane cluster in the methylene chain between the two quaternary ammonium groups. The carborane cluster isomers o-NMB, m-NMB, and p-NMB were tested in animals for neuromuscular block and compared with agents used clinically: rocuronium and decamethonium. All three isomers caused reversible muscle weakness in mice as determined by grip strength and inverted screen tests, with a potency rank of p-NMB > rocuronium > decamethonium > m-NMB > o-NMB. The mechanism of action of the compounds was determined by using the in vitro rat phrenic nerve hemi-diaphragm preparation and electrophysiologic measurements in cells. Neostigmine reversed hemi-diaphragm weakness caused by the three isomers and rocuronium, but not succinylcholine. In electrophysiologic recordings of currents through acetylcholine receptor channels, the carborane compounds did not activate channel activity but did inhibit channel activation by acetylcholine. These results demonstrate that the carborane neuromuscular blocking agents are non-depolarizers in contrast to the depolarizing action of the parent compound.

Asunto(s)

Boranos/farmacología , Fuerza Muscular/efectos de los fármacos , Bloqueantes Neuromusculares/farmacología , Animales , Boranos/síntesis química , Boranos/química , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Bloqueantes Neuromusculares/síntesis química , Bloqueantes Neuromusculares/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo

RESUMEN

We previously reported that a lipophilic N-(4'-hydroxy-3',5'-di-tert-butylbenzyl) derivative (1) of the voltage-gated sodium channel blocker mexiletine, was a more potent sodium channel blocker in vitro and in vivo. We demonstrate that replacing the chiral methylethylene linker between the amine and di-tert-butylphenol with an achiral 1,3-propylene linker (to give (2)) maintains potency in vitro. We synthesized 25 analogues bearing the 1,3-propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV 1.2 and 1.6 channels by high-throughput patch-clamp analysis. Compared to mexiletine, compounds 1 and 2 are highly selective NaV 1.2 inhibitors and >500 times less potent in inhibiting NaV 1.6 channels. On the other hand, a derivative (compound 4) bearing 2,6-dimethoxy groups in place of the 2,6-dimethyl groups found in mexiletine was found to be the most potent inhibitor, but is nonselective against both channels in the tonic, frequency-dependent and inactivated states. In a kindled mouse model of refractory epilepsy, compound 2 inhibited seizures induced by 6 Hz 44 mA electrical stimulation with an IC50 value of 49.9±1.6 mg kg-1 . As established sodium channel blockers do not suppress seizures in this mouse model, this indicates that 2 could be a promising candidate for treating pharmaco-resistant epilepsy.

Asunto(s)

Bencilaminas/síntesis química , Convulsiones/tratamiento farmacológico , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis química , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Bencilaminas/metabolismo , Estabilidad de Medicamentos , Estimulación Eléctrica , Humanos , Mexiletine/metabolismo , Ratones , Estructura Molecular , Técnicas de Placa-Clamp/métodos , Relación Estructura-Actividad , Bloqueadores del Canal de Sodio Activado por Voltaje/metabolismo

RESUMEN

Recent years have seen the emergence into circulation of a growing array of novel psychoactive substances (NPS). Knowledge of the pharmacological profiles and risk liability of these compounds is typically very scarce. Development of chemoinformatic tools enabling prediction of properties within uncharacterised analogues has potential be of particular use. In order to facilitate this, compilation of a chemical inventory comprising known NPS is a necessity. Sourcing a variety of published governmental and analytical reports, a dataset composed of 690 distinct acknowledged NPS, complete with defined chemical structures, has been constructed. This is supplemented by a complementary series of 155 established psychoactive drugs of abuse (EPDA). Classification was performed in accordance with their key molecular structural features, subjective effect profiles and pharmacological mechanisms of action. In excess of forty chemical groupings, spanning seven subjective effect categories and six broad mechanisms of pharmacological action, were identified. Co-occurrence of NPS and EPDA within specific classes was common, showcasing inherent scope both for chemical read-across and for the derivation of structural alerts.

Asunto(s)

Quimioinformática , Bases de Datos de Compuestos Químicos , Drogas Ilícitas/análisis , Psicotrópicos/análisis , Drogas Ilícitas/farmacología , Estructura Molecular , Psicotrópicos/farmacología

RESUMEN

Tau, a microtubule-associated protein playing a key role in a group of neurodegenerative diseases such as Alzheimer's disease, spreads throughout the brain, inducing pathology. A model akin to the spreading of prions has been raised owing to similar characteristics of inducing an abnormal protein conformation as a method of self-amplification, spreading protein aggregates over anatomically linked pathways. The search to identify the "seeds" that induce conformational change has received much attention; however, less is known about the mechanisms by which tau is transmitted from cell to cell, so-called "transcellular spreading". In this review, we gather evidence regarding the spreading of tau throughout the brain and provide an overview of methods by which tau can be released from neurons as well as taken up. Furthermore, we bring together mechanisms of neurotoxicity behind tau spreading. Advancing our understanding about the spreading of tau can guide the search for therapeutic options for multiple neurodegenerative diseases aggregating tau.

Asunto(s)

Tauopatías/fisiopatología , Proteínas tau/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Microglía/metabolismo , Agregación Patológica de Proteínas/fisiopatología , Transcitosis/fisiología

RESUMEN

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

Asunto(s)

Antioxidantes/química , Inhibidores de la Colinesterasa/química , Antagonistas de los Receptores Histamínicos H3/química , Indoles/química , Inhibidores de la Monoaminooxidasa/química , Fármacos Neuroprotectores/química , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacocinética , Antioxidantes/uso terapéutico , Barrera Hematoencefálica/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Colinesterasa/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Diseño de Fármacos , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Indoles/uso terapéutico , Ligandos , Ratones , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacocinética , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/uso terapéutico , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapéutico

RESUMEN

Applying patient friendly and cost-efficient medications in healthcare will be a real challenge in the 21st century. Sugammadex is a selective, yet expensive agent used for the post-surgical reversal of neuromuscular block since 2008. A wide library of cyclodextrin-based follow-ups, having potentially similar affinity towards target aminosteroid type neuromuscular blocking agents has been established. Almost 20 compounds were assessed with respect to in vitro affinity against three commonly applied drugs. Based on the capillary electrophoretic screening, carboxymethylated and sulfobutylated gamma-cyclodextrin derivatives have the potential to be promising lead molecules for their affinity towards pipecuronium was identical or even superior to Sugammadex. Carboxymethylated gamma-cyclodextrin showed efficient and complete reversal of the pipecuronium induced neuromuscular block in an ex vivo rat diaphragm experiment.

Asunto(s)

Bloqueo Neuromuscular , Fármacos Neuromusculares no Despolarizantes/farmacología , Pipecuronio/farmacología , Receptores Artificiales/química , gamma-Ciclodextrinas/farmacología , Animales , Diseño de Fármacos , Masculino , Ratas , Ratas Wistar

RESUMEN

Identification of small molecules that direct neural stem cells (NSCs) into specific cell types would be helpful to understand the molecular mechanisms involved in regulation of NSC fate, and facilitate the development of therapeutic applications. In the current study, we developed and screened small molecules that can modulate the fate of NSCs that are derived from rat fetal cortex. Among these compounds, compounds 5 and 6 successfully differentiated NSCs into astrocytes and neurons, respectively. Compound 5 induced astrocytogenesis by increasing expression of interleukin-6, bone morphogenetic protein 2 and leukemia inhibitory factor and through consequent phosphorylation of signal transducer and activator of transcription 3 and Sma- and Mad-related protein 1/5/8 in NSCs. In addition, compound 5 increased the expression of fibroblast growth factor (FGF) 2 and FGF8 which may regulate the branching and morphology of astrocytes. Taken together, our results suggest that these small molecules can serve as a useful tool to study cell fate determination in NSCs and be used as an inexpensive alternative to cytokines to study mechanisms of astrocytogenesis.

Asunto(s)

Astrocitos/efectos de los fármacos , Citocinas/farmacología , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Células-Madre Neurales/efectos de los fármacos , Organogénesis/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Smad Reguladas por Receptores/metabolismo , Animales , Recuento de Células , Células Cultivadas , Embrión de Mamíferos , Proteína Quinasa 3 Activada por Mitógenos/genética , Modelos Moleculares , Células-Madre Neurales/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/genética , Proteínas Smad Reguladas por Receptores/genética , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad5/genética , Proteína Smad5/metabolismo , Proteína Smad8/genética , Proteína Smad8/metabolismo

RESUMEN

Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups--Mannich phenols and general bases--that are capable of reactivating OPC--inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.

Asunto(s)

Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Descubrimiento de Drogas , Organofosfatos/farmacología , Fenoles/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Estructura Molecular , Organofosfatos/síntesis química , Organofosfatos/química , Relación Estructura-Actividad

RESUMEN

Progressive loss and impaired restoration of neuronal activity are hallmarks of neurological diseases, and new small molecules with neurotrophic activity are in high demand. The militarinone alkaloids and structurally simplified analogues with 4-hydroxy-2-pyridone core structure induce pronounced neurite outgrowth, but their protein target has not been identified. Reported herein is the synthesis of a militarinone-inspired 4-hydroxy-2-pyridone collection, its investigation for enhancement of neurite outgrowth, and the discovery of the stress pathway kinase MAP4K4 as a target of the discovered neuritogenic pyridones. The most potent 4-hydroxy-2-pyridone is a selective ATP-competitive inhibitor of MAP4K4 but not of the other stress pathway related kinases, as proven by biochemical analysis and by a crystal structure of the inhibitor in complex with MAP4K4. The findings support the notion that MAP4K4 may be a new target for the treatment of neurodegenerative diseases.

Asunto(s)

Alcaloides/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Neurogénesis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridonas/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Conformación Molecular , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Piridonas/síntesis química , Piridonas/química , Relación Estructura-Actividad

RESUMEN

Nine novel ß- and γ-carboline derivatives bearing either methyl-, propargyl- or phenethyl-residues at the indole nitrogen were synthesized and tested as potential anti-Alzheimer drugs. Antagonism of recombinantly expressed NMDA receptors, inhibition of cholinesterases, and radical scavenging properties were determined for all compounds. Some were additionally tested in vivo for their ability to reverse scopolamine-induced cognitive impairment in an 8-arm radial maze experiment with rats. For the most promising candidates, the interaction with muscarinic M1 receptors was also investigated. With this set of compounds assays the influence of the scaffold itself and the substituents can be investigated separately. 5-Methyl-γ-carboline (6) was the most potent (0.25 µmol/100 g b.w.) compound in the in vivo test and might be a good starting point for the development of novel anti-Alzheimer drugs.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Ansiolíticos/farmacología , Carbolinas/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Adyuvantes Anestésicos/toxicidad , Enfermedad de Alzheimer/psicología , Animales , Ansiolíticos/química , Carbolinas/química , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/psicología , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/psicología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Escopolamina/toxicidad , Relación Estructura-Actividad

RESUMEN

As a potent neurotrophic agent, the sesquiterpenoid jiadifenolide represents a valuable small-molecule lead for the potential therapeutic treatment of neurodegenerative diseases. A stereocontrolled total synthesis of this densely functionalized natural product is reported, central to which is an adventurous samarium-mediated cyclization reaction to establish the tricyclic core and the adjacent C5 and C6 quaternary stereocenters.

Asunto(s)

Sesquiterpenos/síntesis química , Cristalografía por Rayos X , Ciclización , Estructura Molecular , Oxidación-Reducción , Sesquiterpenos/química , Estereoisomerismo , Compuestos de Vinilo/química

RESUMEN

Two chromo-fluorogenic probes, each based on the boron dipyrromethene core, have been developed for the detection of nerve-agent mimics. These chemosensors display both a color change and a significant enhancement of fluorescence in the presence of diethylcyanophosphonate (DCNP) and diisopropylfluorophosphate (DFP). No interference from other organophosphorus compounds or acids has been observed. Two portable chemosensor kits have been developed and tested to demonstrate its practical application in real-time monitoring.

Asunto(s)

Boro/química , Colorantes/química , Colorantes Fluorescentes , Estructura Molecular , Fosforilación

RESUMEN

Caramboxin: Patients suffering from chronic kidney disease are frequently intoxicated after ingesting star fruit. The main symptoms of this intoxication are named in the picture. Bioguided chemical procedures resulted in the discovery of caramboxin, which is a phenylalanine-like molecule that is responsible for intoxication. Functional experiments in vivo and in vitro point towards the glutamatergic ionotropic molecular actions of caramboxin, which explains its convulsant and neurodegenerative properties.

Asunto(s)

Lesión Renal Aguda/etiología , Enfermedades Transmitidas por los Alimentos/etiología , Frutas/química , Frutas/envenenamiento , Síndromes de Neurotoxicidad/etiología , Neurotoxinas/envenenamiento , Neurotoxinas/toxicidad , Plantas Tóxicas/química , Plantas Tóxicas/envenenamiento , Lesión Renal Aguda/terapia , Animales , Productos Biológicos , Frutas/toxicidad , Hipocampo/efectos de los fármacos , Humanos , Ratas , Ratas Wistar , Diálisis Renal

RESUMEN

Selective activation of the estrogen receptorâ€…ß (ERß) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ERß and ERα, occasionally causing severe side effects. The selective ERß agonist AC-131 has shown efficacy in animal models of Parkinson's disease and neuropathic pain. With the use of AC-131 as template, herein we report the discovery, synthesis, and structure-activity relationship (SAR) study of a new class of dihydrobenzofurans as potent and selective ERß agonists. The SAR was established by enantioselective synthesis, molecular modeling, and whole-cell-based functional assays. The most potent diastereomer, cis-10-SR, was shown to have an EC50 value of <1 nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ERß/ERα selectivity while still maintaining good potency (∼10 nM). In addition, trans-10-SS showed only partial agonist activity (30-60 % Eff.) toward ERα at 10 µM. This unprecedented selectivity could be rationalized by molecular modeling. Compound trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the α- and ß-faces of the binding cavities of ERα and ERß.

Asunto(s)

Benzofuranos/química , Ciclohexanos/química , Diseño de Fármacos , Receptor beta de Estrógeno/agonistas , Compuestos Heterocíclicos con 3 Anillos/química , Fenoles/química , Benzofuranos/síntesis química , Benzofuranos/metabolismo , Cristalografía por Rayos X , Ciclohexanos/síntesis química , Ciclohexanos/metabolismo , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Conformación Molecular , Fenoles/síntesis química , Fenoles/metabolismo , Unión Proteica , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

The (R)-α-lipoyl-glycyl-L-prolyl-L-glutamyl dimethyl ester codrug (LA-GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA-GPE to penetrate the blood-brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA-GPE against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) and H2O2 on the human neuroblastoma cell line SH-SY5Y by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Our results show that codrug 1 is stable at both pH 1.3 and 7.4, exhibits good lipophilicity (log P=1.51) and a pH-dependent permeability profile. Furthermore, LA-GPE was demonstrated to be significantly neuroprotective and to act as an antioxidant against H2O2- and 6-OHDA-induced neurotoxicity in SH-SY5Y cells.

Asunto(s)

Antioxidantes/farmacología , Neuroblastoma/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Oligopéptidos/farmacología , Ácido Tióctico/farmacología , Antioxidantes/química , Antioxidantes/farmacocinética , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Humanos , Peróxido de Hidrógeno/metabolismo , Neuroblastoma/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacocinética , Oligopéptidos/química , Oligopéptidos/farmacocinética , Estrés Oxidativo/efectos de los fármacos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacocinética