Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

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Seeking new polymorphs in pharmaceutical cocrystals: focus on furosemide–ethenzamide
(Royal Society of Chemistry, 2026) Muñoz-Hernández, Estephany; Alarcón-Payer, Carolina; Frontera, Antonio; Prohens López, Rafael; Barbas Cañero, Rafael; Acebedo-Martínez, Francisco Javier; Domínguez-Martín, Alicia; Choquesillo-Lazarte, Duane
Polymorphism remains a critical challenge in the pharmaceutical industry due to its profound impact on the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs). While pharmaceutical multicomponent materials (PMMs) such as cocrystals were initially believed to mitigate polymorphic risks through stabilization via non-covalent interactions, while modulating the properties of different APIs, recent studies have revealed a growing number of polymorphic PMMs, highlighting the need for targeted screening and structural understanding of these materials. In this work, we report the discovery and selective synthesis of a novel polymorph of the furosemide–ethenzamide (FUR–ETZ) cocrystal through kinetic crystallization via fast solvent evaporation. Solid-state characterization confirmed the formation of a polymorph with morphotropic packing relative to the known form, despite maintaining similar molecular conformation and hydrogen bonding motifs. Crystal structure analysis revealed that formII exhibits a lateral layer shift and increased surface polarity, resulting in enhanced aqueous solubility and a slightly higher melting point. In contrast, formI was shown to be thermodynamically more stable, both in dry and aqueous environments, as supported by lattice energy calculations and competitive slurry experiments. These findings underscore the relevance of polymorph screening in PMMs and demonstrate how subtle variations in crystal packing can critically influence the stability and performance of pharmaceutical cocrystals.
A DSC study of the non-isothermal cold crystallization and relaxation effects in ubiquinone and ubiquinol
(Royal Society of Chemistry, 2025-08-04) de Sande, Dafne; Barbas Cañero, Rafael; Bofill, Lídia; Prohens López, Rafael
Cold crystallization effects, the kinetics-dependent crystallization behaviour of amorphous ubiquinone and ubiquinol produced in a series of quenching from-the-melt experiments, have been extensively studied through the combination of differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) techniques under a big diversity of experimental conditions, which has allowed the exploration of their poorly understood polymorphic landscapes. The investigation revealed the existence of a non-previously described polymorph together with a rich set of kinetically dependent transformations, which were observed for the first time by thermal analysis conducted at different heating rates in both oxidized and reduced solid forms of Coenzyme Q10.
A serendipitous synthesis of N,N′‑Diethyloxamide: crystallographic and computational analysis of its solid‑state structure‑Diethyloxamide: crystallogra
(Springer Verlag, 2025-10-04) Marouani, Houda; Jemai, Mahdi; Barceló-Oliver, Miquel; Frontera, Antonio; Prohens López, Rafael
A combined crystallographic/computational analysis focused on the supramolecular features of the crystal structure of N,N′-diethyloxamide (NNDO) is discussed in this work. The studied compound was obtained unexpectedly during the synthesis of a series of salts of cyclic oximes derivatives. In the solid state NNDO is stabilized essentially through a strong N–H···O hydrogen bond but Hirshfeld surface analysis and Density Functional Theory (DFT) calculations were carried out to evalu-ate the strength of the predominant hydrogen bonds observed in the X-ray structure, as well as the secondary C–H···O and C–H···N contacts established between the ethyl groups and the perpendicular dioxamide group. These interactions were further investigated using a combination of Quantum Theory of Atoms in Molecules (QTAIM), Non-Covalent Interaction Plot (NCIplot) and natural bond orbital (NBO) analysis computational tools, and were rationalized using Molecular Elec-trostatic Potential (MEP) surface, electron localization function (ELF), localized orbital locator (LOL) and Fukui function calculations. The insights gathered in this study enrich the understanding of the factors governing crystal packing in amides and related compounds.
Deciphering supramolecular synthons in OXYMA-B salts: Crystallographic characterization and theoretical evaluation of hydrogen bond networks
(Elsevier B.V., 2026-02-15) Jemai, Mahdi; Barbas Cañero, Rafael; Barceló-Oliver, Miquel; Marouani, Houda; Albericio Palomera, Fernando; Frontera, Antonio; Prohens López, Rafael
Four new crystal structures of OXYMA-B in its anionic form have been synthesized and structurally characterized via single-crystal X-ray diffraction. The new salts incorporate protonated amine-based cations including 1-phenylpiperazine (1PP), 1,4-dioxa-8-azaspiro[4.5]decane (DASD), ethylenediamine (ETDA), and pyrrolidine (Pyr), which function as efficient hydrogen bond (H-bond) donors. The electron-rich nature of the OXYMA-B anion provides multiple sites for H-bond acceptance, leading to diverse supramolecular synthons including (5),(6), (8) and(12). The theoretical component of this study is based on density functional theory (DFT) calculations to dissect and characterize the individual H-bonded synthons using the quantum theory of atoms in molecules (QTAIM) framework. Additionally, interaction energies of discrete H-bonds have been quantified to rationalize their strength and directional preferences, showing that directional NH···O bonds contribute the most to the stability of the assemblies, with ancillary contacts playing a secondary but supportive role. The total interaction energies range from –34.0 to –50.0 kcal/mol, underscoring the critical role of hydrogen bonding in dictating the supramolecular architectures. This combined experimental–computational approach sheds light on the structural determinants driving supramolecular organization in OXYMA-B-based salts and highlights their potential for crystal engineering applications.
New and promising type of leukotriene B4 (LTB4) antagonists based on the 1,4-benzodioxine structure
(Elsevier Masson SAS, 2023-04-06) Bouissane, Latifa; Khouili, Mostafa; Coudert, Gérard; Pujol Dilmé, M. Dolors; Guillaumet, Gérald
New leukotriene B4 (LTB4) antagonists have been synthesized that can be considered as potential anti-inflammatory drugs. Structures containing the dioxygenated nucleus of 1,4-benzodioxine constitute a potential group of leukotriene B4 (LTB4) antagonists. The objective of this study was to access efficient and selective LTB4 antagonists as a way to elucidate the role of LTB4 in inflammatory processes and therefore allow the development of new types of structures based on 1,4-benzodioxine. Forty-one new 1,4-benzodioxine molecules substituted at different positions of the heterocyclic nucleus were synthesized to determine the minimum structural requirements by studying structure-activity relationships. Eighteen of them were tested in vitro and in vivo for their anti-inflammatory activity related to the antagonist character of LTB4. Pharmacological tests have shown satisfactory in vitro activity for compounds 24b, 24c and 24e with IC50's of 288, 439, 477 nM respectively. The results of the in vivo tests, carried out with the compound that presented greater activity in the in vitro tests 24b, have shown significant anti-inflammatory properties.
SnCl2-catalyzed Kabachnik-Fields of alfa-aminophosphonates with potent antioxidant activity
(Royal Society of Chemistry, 2025-12-12) Hibot, Achraf; Hamri, Salha; Hafid, Abderrafia; Khouili, Mostafa; Pujol, Maria Dolors
A novel and efficient method for synthesizing a-aminophosphonates was developed through a Kabachnik–Fields multicomponent reaction using 6-aminocoumarin or 6-aminobenzodioxane, benzaldehyde, triethylphosphite, and a catalytic amount of SnCl2 in ethanol. The resulting 25 compounds 1a–l (71–92%) and 6a–m (45–96%) were obtained in moderate to excellent yields. Antioxidant activity, assessed via the FRAP andCUPRAC assays, the results demonstrated that several of these compounds exhibit comparable or evensuperior reducing power to ascorbic acid, particularly at low concentrations. These findings underscorethe potential of these a-aminophosphonates as promising antioxidant agents for future applications.ADME analysis predicts good oral bioavailability, limited brain and skin penetration, and potential CYP450inhibition.
The effect of aerobic and resistance training in patientswith type 2 diabetes on vitamin D(DIAVITEX): a study protocol
(Frontiers Media, 2026-01-05) Guerra Balic, Miriam; Montané Mogas, Joel; Dardashtipour, Elnaz; Canivell Fusté, Silvia; Azarbayjani, Mohammad Ali; Fuente Vidal, Andrea; Surroca, Aina; Gascón Lecha, M. Pilar; Mestres Miralles, Concepción; Antón, Alicia; Peña-Mateo, Maria José; Carrillo-Alvarez, Elena; Canudas Teixidó, Anna-Maria
Introduction: Aerobic and resistance training can effectively improve clinicalmanagement in people with type 2 diabetes (T2D). Low vitamin D (VitD) levels areassociated with T2D risk and metabolic disturbances, and may help reduce thisrisk, particularly in individuals with low VitD levels. In this line, many individualswith T2D, who may also be older adults or have osteoporosis, regularly includeVitD treatment in their healthcare routines. Although the impact of exercisehas been extensively studied, its effect on diabetic patients taking VitD remainslimited. The aim of this study is to investigate the effect of aerobic and resistancetraining on clinical parameters in patients with T2D already taking VitD.Methods: The DIAVITEX study is a randomized controlled superiority trial, withfour parallel arms, including 80 individuals with T2D. Patients will be selectedat the Primary Care Centers and stratified according to their pre-existingVitD treatment. Participants will subsequently be randomized to the exerciseintervention or control as follows: Group 1, Exercise + VitD users (n = 20);Group 2, Exercise + VitD non-users (n = 20); Group 3, VitD only (no exercise)(n = 20); and Group 4, Control (No VitD & No Exercise) (n = 20). In this study,a sarcoplasm-stimulating training program will be carried out online, threesessions per week for a total of 16 weeks. Before and after the physical activitysubjects will perform fitness and blood tests. Nutritional education programswill be provided to normalize their diets for study consistency. The primaryendpoint of the trial is the change in HOMA-IR index from baseline to week 16.Secondary endpoints include changes in HbA1c, lipid profile, body composition,and inflammatory biomarkers.Discussion: Expected improvements in insulin resistance, glycated hemoglobin,lipid profile, and inflammatory markers are anticipated following a 16-weekregimen of exercise in patients with T2D on VitD.Clinical trial registration: The study was registered on September 21, 2024,with the identifier number NCT06081387, https://clinicaltrials.gov/study/NCT06081387.
Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
(Elsevier B.V., 2025-07-15) Bentanachs Raset, Roger; Ramírez-Carrasco, Patricia; Braster, Bianca; Emmanouilidou, Anastasia; Mujica, Endrina; Rodrigo-Calvo, Maite; Rodríguez, Carla; Roglans i Ribas, Núria; den Hoed, Marcel; Laguna Egea, Juan Carlos; Alegret i Jordà, Marta
Drug combination and repurposing are potential therapeutic strategies for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we have demonstrated that, in rats, both pemafibrate and telmisartan reverse hepatic steatosis induced by a high-fat, high-fructose diet. Pemafibrate attenuated liver steatosis via a PPARα-mediated increase in fatty acid catabolism, while the antisteatotic response to telmisartan did not rely on PPAR modulation. Our results in rats and in a zebrafish larva model of liver lipid accumulation suggest that part of telmisartan's antisteatotic effects are driven through the blockade of the angiotensin II type 1 receptor, along with a reduction in the expression of several lipogenic genes, which also contributes to some extent. Telmisartan's response is mediated by the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) expression. Liver metabolomic analysis revealed that by increasing PCK1, telmisartan diverted the metabolic flux of fructose from lipid towards glucose synthesis, which was subsequently fueled to the polyol pathway, thereby preserving glucose homeostasis. Moreover, telmisartan increased the hepatic levels of spermine and spermidine, which may counteract the putative detrimental effects caused by the accumulation of metabolites of the polyol route. Targeting different intrahepatic pathways, both PPAR-dependent and independent, the combination of pemafibrate and telmisartan, each at half the individual dose, was equally effective as the full dose of either drug alone to reduce liver lipid accumulation in the rat model. Our findings support the repurposing potential of these drugs, with the additional advantage of addressing both hepatic and cardiometabolic MASLD-associated complications.
Walnut-enriched diet increases the association of LDL from hypercholestero lemic men with human HepG2 cells
(American Society for Biochemistry and Molecular Biology, 2001) Muñoz, Sonia; Merlos Roca, Manuel; Zambón, Daniel; Rodríguez, Carmen; Sabaté, Joan; Ros Rahola, Emilio; Laguna Egea, Juan Carlos
In a randomized, cross-over feeding trial involving 10 men with polygenic hypercholesterolemia, a control, Mediterranean-type cholesterol-lowering diet, and a diet of similar composition in which walnuts replaced approximately 35% of energy from unsaturated fat, were given for 6 weeks each. Compared with the control diet, the walnut diet reduced serum total and LDL cholesterol by 4.2% (P = 0.176), and 6.0% (P = 0.087), respectively. No changes were observed in HDL cholesterol, triglycerides, and apolipoprotein A-I levels or in the relative proportion of protein, triglycerides, phospholipids, and cholesteryl esters in LDL particles. The apolipoprotein B level declined in parallel with LDL cholesterol (6.0% reduction). Whole LDL, particularly the triglyceride fraction, was enriched in polyunsaturated fatty acids from walnuts (linoleic and alpha-linolenic acids). In comparison with LDL obtained during the control diet, LDL obtained during the walnut diet showed a 50% increase in association rates to the LDL receptor in human hepatoma HepG2 cells. LDL uptake by HepG2 cells was correlated with alpha-linolenic acid content of the triglyceride plus cholesteryl ester fractions of LDL particles (r(2) = 0.42, P < 0.05). Changes in the quantity and quality of LDL lipid fatty acids after a walnut-enriched diet facilitate receptor-mediated LDL clearance and may contribute to the cholesterol-lowering effect of walnut consumption.
“Synthetic Map”: A Graphic Organizer Inspired by Artificial Neural Network Paradigms for Learning Organic Synthesis.
(Division of Chemical Education of the American Chemical Society., 2024-09-09) Luque Corredera, Carlos; Bartolomé, Elena; Bradshaw, Ben
Organic Chemistry is widely recognized as a challenging subject, with the design of syntheses and retrosyntheses identified as particularly difficult tasks. Inspired by the success of artificial neural networks in machine learning, we propose a framework that leverages similar principles to enhance the teaching and learning of organic synthesis. In this paper, we introduce a novel teaching tool, the “Synthetic Map”, that attempts to visually recreate an expert’s mental map and conceptual understanding of organic synthesis built over years of experience. The educational benefits of the Synthetic Map were evaluated through its implementation in an Organic Chemistry course of a Pharmacy degree over two years. The new tool promoted students’ learning by providing a mental organizer fostering a deeper understanding of the subject and empowering students to design and execute effective synthetic strategies.
Sex Differences Affect the NRF2 Signaling Pathway in the Early Phase of Liver Steatosis: A High-Fat-Diet-Fed Rat Model Supplemented with Liquid Fructose
(MDPI, 2024-08-01) Di Veroli, Benedetta; Bentanachs Raset, Roger; Roglans i Ribas, Núria; Alegret i Jordà, Marta; Giona, Letizia; Profumo, Elisabetta; Berry, Alessandra; Saso, Luciano; Laguna Egea, Juan Carlos; Buttari, Brigitta
Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD.
Developmental neurotoxicity evaluation of di(2-ethylhexyl) phthalate (DEHP) and three alternative plasticizers in human neurospheres
(Elsevier , 2026-01-07) Illa Armengol, Míriam; Seeger, Brettina; Klose, Jördis; Kühne, Britta Anna; Muñoz-Torrero López-Ibarra, Diego; Koch, Katharina; Fritsche, Ellen; Barenys Espadaler, Marta
Plasticizers like di-(2-ethylhexyl) phthalate (DEHP) are commonly used in medical devices to enhance plastic flexibility. DEHP is classified as a CMR1b substance due to its adverse effects on reproduction and fertility, and it has been linked to neurodevelopmental disorders such as ADHD, autism spectrum disorder, and learning disabilities. While DEHP is scheduled for phase-out by 2030, data on the developmental neurotoxicity (DNT) of alternative plasticizers remain scarce. We evaluated the DNT potential of DEHP and three alternative plasticizers: di-(2-ethylhexyl) terephthalate (DEHT), di-(2-ethylhexyl) adipate (DEHA), and tris-(2-ethylhexyl) trimellitate (TOTM), aiming to identify safer substitutes, particularly for neonates in neonatal intensive care units (NICUs). The human Neurosphere Assay was used to assess plasticizer effects on seven key neurodevelopmental processes: neural progenitor cell (NPC) proliferation, migration of radial glia, neurons, and oligodendrocytes, neurite outgrowth, and differentiation of neurons and oligodendrocytes. Concentration-response analyses provided benchmark concentrations (BMCs) and lowest observed adverse effect concentrations (LOAECs). Gene expression profiling provided mechanistic insights, and toxicity was ranked using the most sensitive endpoint (MSE) and ToxPi Tool. DEHP and TOTM showed the highest DNT potential, with NPC proliferation as the MSE. DEHT impacted oligodendrocyte differentiation, while no BMC was determined for DEHA within the tested concentrations. Considering an exposure scenario in NICUs, the estimated neonatal DEHP plasma levels exceeded the LOAEC for NPC proliferation, raising concerns for DNT. Overall, DEHA emerged as the least hazardous alternative for neurodevelopment, highlighting the value of combined human-relevant in vitro phenomics and human biomonitoring for DNT hazard evaluation.
First-Generation Synthetic Cathinones Produce Arrhythmia in Zebrafish Eleutheroembryos: A New Approach Methodology for New Psychoactive Substances Cardiotoxicity Evaluation
(MDPI, 2023-09-08) Teixidó Condomines, Elisabet; Riera-Colomer, Clara; Raldúa, Demetrio; Pubill Sánchez, David; Escubedo Rafa, Elena; Barenys Espadaler, Marta; López Arnau, Raúl
The increasing number of new psychoactive substances (NPS) entering the illicit drug market, especially synthetic cathinones, as well as the risk of cardiovascular complications, is intensifying the need to quickly assess their cardiotoxic potential. The present study aims to evaluate the cardiovascular toxicity and lethality induced by first-generation synthetic cathinones (mephedrone, methylone, and MDPV) and more classical psychostimulants (cocaine and MDMA) in zebrafish embryos using a new approach methodology (NAM). Zebrafish embryos at 4 dpf were exposed to the test drugs for 24 h to identify drug lethality. Drug-induced effects on ventricular and atrial heart rate after 2 h exposure were evaluated, and video recordings were properly analyzed. All illicit drugs displayed similar 24 h LC₅₀ values. Our results indicate that all drugs are able to induce bradycardia, arrhythmia, and atrial-ventricular block (AV block), signs of QT interval prolongation. However, only MDPV induced a different rhythmicity change depending on the chamber and was the most potent bradycardia and AV block-inducing drug compared to the other tested compounds. In summary, our results strongly suggest that the NAM presented in this study can be used for screening NPS for their cardiotoxic effect and especially for their ability to prolong the QT intervals.
A gram-scale route to phlegmarine alkaloids: rapid total synthesis of (-)-cermizine B
(Royal Society of Chemistry, 2014-04-03) Bradshaw, Ben; Luque Corredera, Carlos; Bonjoch i Sesé, Josep
The synthesis of the Lycopodium alkaloid ( )-cermizine B (1), which establishes its absolute configuration, is achieved by combining asymmetric organocatalysis and an uninterrupted eight-step reaction sequence, followed by a final reduction step. This ''pot-economy'' strategy provides access to the cis-phlegmarine stereo parent embedded in 1 for the first time, rapidly and on a gram-scale.
cis-Decahydroquinolines via asymmetric organocatalysis:application to the total synthesis of lycoposerramine Z
(American Chemical Society, 2012-12-27) Bradshaw, Ben; Luque Corredera, Carlos; Bonjoch i Sesé, Josep
Aquest article és el primer que es va obtenir en el context de la tesi doctoral. Es va publicar a finals de 2012 - principis de 2013. Es descriu
el primer dels resultats que es varen obtenir, i que va ser la clau per la obtenció dels articles posteriors (anys 2013 i 2014). Descriu, en
concret, el descobriment d'una nova reacció en síntesis química, que inclou 3 reaccions en un sol pas sintètic, en un procediment anomenat
"one-pot procedure". Aquesta reacció permet accedir, de forma directa i selectiva, a una estructura mare (o building block) que és un
heterocicle anomenat "decahidroquinolina", que a la seva vegada, és un intermedi avançat per la síntesis total d'una família d'alcaloides
anomenada flegmarina. A més, aquest procediment permet la obtenció d'un compost bi-cíclic (com ho és la decahidroquinolina) desde
material comercial i acíclic. El procés, te una selectivitat i una puressa superiors al 99% (amb traces d'altres compostos anàlegs), i per tant,
suposa un mètode molt eficient per accedir a aquesta familia d'estructures naturals.
Towards a glutathione-cleavable azobenzene linker for antibody–drug conjugates
(Royal Society of Chemistry, 2025-10-28) Kapun, Mia; Patel, Roshan; Park, Mahri; Pérez Areales, Francisco Javier; Kostadinova, Kristina A.; Wharton, Thomas; Carroll, Jason S.; Spring, David R.
Herein we describe the development of a novel azobenzene-containing glutathione-cleavable linker for use in antibody–drug conjugates (ADCs). This linker demonstrated efficient payload release under elevated glutathione levels while maintaining stability in human plasma. An anti-HER2 ADC incorporating this linker exhibited potent in vitro cytotoxicity and selective activity towards HER2-positive cell lines.
Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights
(American Chemical Society, 2025-12-02) Kastner, Nina; Nadal-Gratacós, Núria; Shacham, Sharon; Cuccurazzu, Bruna; Halberstadt, Adam L.; McCorvy, John D.; Stockner, Thomas; Meyer, Markus R.; López Arnau, Raúl; Grill, Matthias; Sitte, Harald H.; Hemmer, Selina; Alves da Silva, Leticia; McKee, John L.; Hell, Tamara; Cicalese, Giulia; Holy, Marion; Kooti, Fatemeh; Jäntsch, Kathrin; Baron, Roland
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, shows promise in treating depression and post-traumatic stress disorder (PTSD), resulting in breakthrough status. However, concerns regarding MDMA's abuse potential and cytotoxicity have sparked interest in developing safer analogues with similar therapeutic benefits. This study investigated the pharmacological properties of MDMA analogues in which the 1,3-benzodioxole group is replaced by a 1,3-benzoxathiole, termed SDA and SDMA, compared to MDA and MDMA through in silico, in vitro, and in vivo assays. In vitro experiments using human embryonic kidney (HEK293) cells examined the interactions with monoamine transporters. SDA and SDMA showed similar profiles to MDMA at the serotonin transporter (SERT), while both inhibited dopamine (DAT) and norepinephrine (NET) transporters more potently, in line with in silico molecular docking fitness scores of binding. SDA and SDMA also showed increased potency in evoking efflux through SERT and DAT acting as partial releasers. SDA and SDMA exhibited a similar interaction profile with 5-HT₂ receptors compared with their respective analogues. Metabolism studies revealed faster clearance rates for SDA and SDMA, in contrast to MDA and MDMA, which exhibited only weak degradation. In contrast to MDMA's rewarding effects, SDMA did not induce significant effects in mice, while SDA only produced a significant preference for the drug-paired compartment at the lowest dose tested. Moreover, while SDMA shares similar locomotor and hyperthermic profiles as MDMA in mice, SDA induced increased hyperlocomotion and more sustained hyperthermia. In conclusion, these findings suggest that SDMA, with enhanced metabolic profiles and reduced abuse potential, is a promising candidate for further studies.
Neuroprotective effects of N-acetylcysteine-amide (AD4) in a Survival Mouse Model of Paraoxon Intoxication: Targeting Oxidative Stress, Neuroinflammation and Memory Impairments.
(MDPI, 2025-12-06) Urquizu, Edurne; Cuiller, Marine; Papadopoulou, Georgia; Pubill Sánchez, David; Raldúa, Demetrio; Camarasa García, Jordi; Escubedo Rafa, Elena; López-Arnau, Raúl
Neurotoxicity induced by organophosphorus (OP) compounds such as paraoxon (POX)
leads to severe brain damage and cognitive impairments. Although current treatments
alleviate acute cholinergic symptoms, they fail to address secondary neurotoxicity. This
study investigated the therapeutic potential of N-acetylcysteine-amide (AD4), a blood–
brain-barrier permeable antioxidant, in a survival mouse model of acute POX intoxication.
Male Swiss CD-1 mice received POX (4 mg/kg) followed by standard emergency therapy
(atropine, pralidoxime and diazepam). AD4 (150 mg/kg) was administered 2 and 6 h
post-exposure. AD4 treatment effectively prevented oxidative stress by reducing lipid
peroxidation and restoring the expression in hippocampus (HP) and/or prefrontal cortex
(PFC) of key antioxidant enzymes such as glutathione peroxidase-1 (GPx-1) and catalase
(CAT) suppressed by POX acute exposure. Moreover, AD4 attenuated neuroinflammation
in specific hippocampal subregions, as evidenced by reduced Glial Fibrillary Acidic Protein
(GFAP) and Ionized Calcium Binding Adaptor Molecule 1 (Iba-1) immunoreactivity. Im-
portantly, AD4 also rescued recognition memory deficits, as assessed by the Novel Object
Recognition Test (NORT). In summary, these findings demonstrate that AD4 mitigates
oxidative stress, neuroinflammation, and cognitive dysfunction following acute POX in-
toxication, supporting its potential as an adjuvant therapy for mitigating the secondary
neurotoxicity derived from organophosphorus poisoning.
Mg/Fe-LDH: An efficient promoter for the synthesis of tetrahydrospiro[pyrazole-4,5′-pyrazolo[3,4-b]pyridine] derivatives
(Elsevier, 2024-03-10) Hibot, Achraf; Fadili, Hicham; Hafid, Abderrafia; Lebreton, Jacques; Pujol, Maria Dolors; Khouili, Mostafa
The synthesis of tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivativesusing Mg/Fe-LDH as a heterogeneous catalyst was reported. This methodology usedfor the condensation of pyrazolones with aldehydes in a basic medium and with thepresence of the Mg/Al-LDH catalyst presents many benefits, such as the fact of using areusable and low-cost catalyst, environmentally friendly conditions, time short reactiontimes and excellent yields. It has been verified and confirmed that the catalyst isrelatively stable and allows its reuse without additional treatment. Condensation hasbeen carried out with different aldehydes and bis-pyrazolone derivatives have beenobtained with yields ranging from 71 to 91% of purified product. The stereo impedanceof the adduct formed prevents subsequent condensation.
3,4-Methylenedioxymethamphetamine, synthetic cathinones and psychedelics: From recreational to novel psychotherapeutic drugs
(Frontiers Media, 2022-10-03) López Arnau, Raúl; Camarasa García, Jordi; Carbó Banús, Marcel·lí; Nadal-Gratacós, Núria; Puigseslloses, Pol; Espinosa-Velasco, María; Urquizu, Edurne; Escubedo Rafa, Elena; Pubill Sánchez, David
The utility of classical drugs used to treat psychiatric disorders (e.g.,antidepressants, anxiolytics) is often limited by issues of lack of efficacy, delayed onset of action or side effects. Psychoactive substances have a long history of being used as tools to alter consciousness and as a gateway to approach the unknown and the divinities. These substances were initially obtained from plants and animals and more recently by chemical synthesis, and its consumption evolved toward a more recreational use, leading to drug abuse-related disorders, trafficking, and subsequent banning by the authorities. However, these substances, by modulation of certain neurochemical pathways, have been proven to have a beneficial effect on some psychiatric disorders. This evidence obtained under medically controlled conditions and often associated with psychotherapy, makes these substances an alternative to conventional medicines, to which in many cases the patient does not respond properly. Such disorders include post-traumatic stress disease and treatment-resistant depression, for which classical drugs such as MDMA, ketamine, psilocybin and LSD, among others, have already been clinically tested, reporting successful outcomes. The irruption of new psychoactive substances (NPS), especially during the last decade and despite their recreational and illicit uses, has enlarged the library of substances with potential utility on these disorders. In fact, many of them were synthetized with therapeutic purposes and were withdrawn for concrete reasons (e.g., adverse effects, improper pharmacological profile). In this review we focus on the basis, existing evidence and possible use of synthetic cathinones and psychedelics (specially tryptamines) for the treatment of mental illnesses and the properties that should be found in NPS to obtain new therapeutic compounds.

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