A5078484971- Receptor Mechanisms and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Synthesis and Biological Evaluation
- Cancer, Lipids, and Metabolism
- Chemical synthesis and alkaloids
- Peroxisome Proliferator-Activated Receptors
- Inflammatory mediators and NSAID effects
- Nicotinic Acetylcholine Receptors Study
- Phenothiazines and Benzothiazines Synthesis and Activities
- Neuropeptides and Animal Physiology
- Neuroscience and Neuropharmacology Research
- Pharmacological Receptor Mechanisms and Effects
- Synthesis of heterocyclic compounds
- Cancer, Hypoxia, and Metabolism
- Catalytic C–H Functionalization Methods
- Synthesis and Reactions of Organic Compounds
- Radical Photochemical Reactions
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Synthesis and biological activity
- Multicomponent Synthesis of Heterocycles
- Plant biochemistry and biosynthesis
- Protein Structure and Dynamics
- Treatment of Major Depression
- Monoclonal and Polyclonal Antibodies Research
Universidad Complutense de Madrid
2011-2024
Universitat Autònoma de Barcelona
2002-2009
Institut d'Investigació Biomèdica de Girona
2009
Institut Català d'Oncologia
2009
Universitat de Barcelona
2009
University of Girona
2009
Institut d'Investigació Biomédica de Bellvitge
2009
National University of Distance Education
1994-2005
Weizmann Institute of Science
2000
University of Cambridge
1996
PURPOSE: Fatty acid synthase (FASN) is overexpressed in human breast carcinoma. The natural polyphenol (-)-epigallocatechin-3-gallate blocks vitro FASN activity and leads to apoptosis cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, vivo, does not decrease body weight. We synthesized a panel of new polyphenolic compounds tested their models. EXPERIMENTAL DESIGN: evaluated the cell growth (SK-Br3, MCF-7, MDA-MB-231), [as assessed by cleavage...
Inhibiting the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of breast carcinoma cells, and this is linked human epidermal growth factor receptor 2 (HER2) signaling pathways in models simultaneous expression FASN HER2. In a xenograft model cells that are FASN+ HER2+, we have characterised anticancer activity toxicity profile G28UCM, lead compound novel family synthetic inhibitors. vitro, analysed cellular molecular interactions combining G28UCM with anti-HER drugs. Finally, tested...
Fatty acid synthase (FASN) is a lipogenic enzyme that highly expressed in different human cancers. Here we report the development of new series polyphenolic compounds 5-30 have been evaluated for their cytotoxic capacity SK-Br3 cells, breast cancer cell line with high FASN expression. The an IC(50) < 50 μM tested ability to inhibit activity. Among them, derivative 30 blocks 90% activity at low concentration (4 μM), broad panel tumor induces apoptosis, and activation HER2, AKT, ERK pathways....
Ovarian cancer (OC) is caused by genetic aberrations in networks that control growth and survival. Importantly, aberrant metabolism interacts with oncogenic signaling providing additional drug targets. Tumors overexpress the lipogenic enzyme fatty acid synthase (FASN) are inhibited FASN blockers, whereas normal cells FASN‐negative FASN‐inhibitor‐resistant. Here, we demonstrate this holds true when ovarian/oviductal reside their autochthonous tissues, culture they express...
Receptor-PI3K-mTORC1 signaling and fatty acid synthase (FASN)-regulated lipid biosynthesis harbor numerous drug targets are molecularly connected. We hypothesize that unraveling the mechanisms of pathway cross-talk will be useful for designing novel co-targeting strategies ovarian cancer (OC). The impact receptor-PI3K-mTORC1 onto FASN is already well-characterized. However, reverse actions-from towards receptor-PI3K-mTORC1-are still elusive. show FASN-blockade impairs at multiple levels....
Forty-five structurally diverse 5-hydroxytryptamine6 receptor (5-HT6R) antagonists were selected to develop a 3D pharmacophore model with the Catalyst software. The structural features for antagonism at this are positive ionizable atom interacting Asp3.32, hydrogen bond acceptor group Ser5.43 and Asn6.55, hydrophobic site residues in pocket between transmembranes 3, 4, 5, an aromatic-ring Phe6.52.
On the basis of our previously described pharmacophore model for serotonin 5-HT6 receptor (5-HT6R) antagonists, we have designed, synthesized, and pharmacologically characterized a series benzimidazole derivatives 1−20 that represent new family potent antagonists at human 5-HT6R. Site-directed mutagenesis β2-adrenoceptor-based homology 5-HT6R were used to predict mode binding antagonist SB-258585 synthesized ligands. Substitution W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 block...
Serotonin 5-HT6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules drug class treatment Alzheimer's disease and other pathologies associated with memory deficiency. As part our efforts receptor, benzimidazole-based compounds have designed synthesized. Site-directed mutagenesis homology models show importance halogen bond interaction between chlorine atom identified herein...
We present in this study an optimization of a preliminary pharmacophore model for 5-HT7R antagonism, with the incorporation recently reported ligands and using efficient procedure CATALYST program. The consists five features: positive ionizable atom (PI), H-bonding acceptor group (HBA), three hydrophobic regions (HYD). This has been supported by design, synthesis, biological evaluation new naphtholactam naphthosultam derivatives general structure I (39−72). A systematic structure−affinity...
We report the synthesis of a new set compounds general structure I (1−20) with structural modifications in pharmacophoric elements previously reported lead UCM-5600. The derivatives have been evaluated for binding affinity at 5-HT7 and 5-HT1A receptors. influence different features terms 5-HT7/5-HT1A receptor selectivity was analyzed by computational simulations complexes between β2-based 3-D models these Compound 18 (HYD1 = 1,3-dihydro-2H-indol-2-one; spacer −(CH2)4−; HYD2 + HYD3...
The 5-HT2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In search allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications identified hit VA240 in synthesized analogues 6–41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement serotonin...
Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in therapy type-2 diabetes and are being considered for reducing food intake obesity. Potential advantages small molecules acting as positive allosteric modulators (PAMs) GLP-1R, including oral administration reduced unwanted effects, could improve utility this class drugs. Here, we describe discovery compound 9...
A series of 48 bicyclohydantoin−phenylpiperazines (1−4) with affinity for 5-HT1A and α1 receptors was subjected to three-dimensional quantitative structure−affinity relationship analysis using comparative molecular field (CoMFA), in order get insight into the structural requirements that are responsible 5-HT1A/α1 selectivity. Good models (high cross-validation correlations predictive power) were obtained receptors. The resulting 3D-QSAR rationalize steric electrostatic factors which modulate...
A series of new bicyclohydantoin−arylpiperazines was prepared and evaluated for affinity at 5-HT1A, α1, D2 receptors. Most the compounds showed very low receptors, most them demonstrated moderate to high 5-HT1A α1 receptor binding sites. SAR observations indicated that length alkyl chain between arylpiperazine hydantoin moiety is great importance 5-HT1A/α1 selectivity, n = 1 being optimal value. Compound 1h,...
We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT1AR affinity selectivity over α1-adrenoceptors. The selective ligands contain hydantoin (m = 0) or diketopiperazine 1) moiety an arylpiperazine separated by one methylene unit (n 1). aryl substituent the piperazine (Ar) consists different benzofused rings mimicking favorable voluminous substituents at ortho meta positions predicted 3D-QSAR analysis in previously reported I. In particular,...
We report the synthesis of new compounds 4–35 based on structural modifications different moieties previously described lead UCM-2550. The nonpiperazine derivatives, representing second-generation agonists, were assessed for binding affinity, selectivity, and functional activity at 5-HT1A receptor (5-HT1AR). Computational β2-based homology models ligand–receptor complexes used to explain observed structure–affinity relationships. Selected candidates also evaluated their potential in vitro...
We report the synthesis of new compounds 4–35 based on two different openings (A and B) chromane ring present in previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized were assessed for binding affinity, selectivity, functional activity at 5-HT1AR. Selected candidates resulting from B opening also evaluated their potential antinociceptive effect vivo pharmacokinetic properties vitro. Analogue 19...
A new series of azabicyclic benzimidazole-4-carboxamides 2−21 and -carboxylates 22−30 were synthesized evaluated for binding affinity at serotoninergic 5-HT3 5-HT4 receptors in the CNS. Most compounds exhibited high or very site low to no significant receptor. SAR observations indicated that a halogen atom 6-position nitro group 7-position benzimidazole ring is best substitution pattern 5-HT3/5-HT4 selectivity, as well this ring. (S)-(−)-N-(Quinuclidin-3-yl)benzimidazole-4-carboxamides 2, 8,...
In this work, we report the design and synthesis of a set fluorescent probes targeting human 5-HT1A receptor (h5-HT1AR). Among synthesized compounds, derivative 4 deserves special attention as being high-affinity ligand (K i = 2 nM) with good properties (I em > 1000 au fluorescence quantum yield, Φf, 0.26), which enables direct observation h5-HT1AR in cells. Thus, it represents first efficacious probe for specific labeling Our results provide basis introduction variety tags scaffolds G...
The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, addition orthosteric site, allowed us obtain 5-HT7R antagonist 6 endowed with high affinity (Ki = 0.7 nM) and significant 5-HT1AR selectivity (ratio >1428). Compound exhibits vivo antidepressant-like effect (1 mg/kg, ip) mediated by 5-HT7R, which reveals its interest as putative research tool or pharmaceutical depression disorders.
Abstract Determination of the targets a compound remains an essential aspect in drug discovery. A complete understanding all binding interactions is critical to recognize advance both therapeutic effects and undesired consequences. However, polypharmacology many drugs currently clinical development still unknown, especially case G protein‐coupled receptor (GPCR) ligands. In this work we have developed chemoproteomic platform based on use chemical probes explore target profile biological...
A three-dimensional quantitative structure−affinity relationship study (3D-QSAR), using the comparative molecular field analysis (CoMFA) method, and subsequent computational simulation of ligand recognition have been successfully applied to explain binding affinities for 5-HT4 receptor (5-HT4R) a series benzimidazole-4-carboxamides carboxylates derivatives 1−24. The Ki values these compounds are in range from 0.11 10 000 nM. derived 3D-QSAR model shows high predictive ability (q2 = 0.789 r2...