Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Toward biophysical probes for the 5-HT3 receptor: structure-activity relationship study of granisetron derivatives.

ABSTRACT: This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT(3)A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT(3)A receptors in mammalian cells.

SUBMITTER: Vernekar SK

PROVIDER: S-EPMC4166935 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Toward biophysical probes for the 5-HT3 receptor: structure-activity relationship study of granisetron derivatives.

Vernekar Sanjeev Kumar V SK Hallaq Hasan Y HY Clarkson Guy G Thompson Andrew J AJ Silvestri Linda L Lummis Sarah C R SC Lochner Martin M

Journal of medicinal chemistry 20100301 5

This report describes the synthesis and biological characterization of novel granisetron derivatives that are antagonists of the human serotonin (5-HT(3)A) receptor. Some of these substituted granisetron derivatives showed low nanomolar binding affinity and allowed the identification of positions on the granisetron core that might be used as attachment points for biophysical tags. A BODIPY fluorophore was appended to one such position and specifically bound to 5-HT(3)A receptors in mammalian cel ...[more]

PMID: 20146481

Similar Datasets

The 5-HT3 receptor--the relationship between structure and function.

Project description:The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. Here, we review the relationship between the structure and the function of the 5-HT3 receptor. 5-HT3A and 5-HT3B subunits are well established components of 5-HT3 receptors but additional HTR3C, HTR3D and HTR3E genes expand the potential for molecular diversity within the family. Studies upon the relationship between subunit structure and the ionic selectivity and single channel conductances of 5-HT3 receptors have identified a novel domain (the intracellular MA-stretch) that contributes to ion permeation and selectivity. Conventional and unnatural amino acid mutagenesis of the extracellular domain of the receptor has revealed residues, within the principle (A-C) and complementary (D-F) loops, which are crucial to ligand binding. An area requiring much further investigation is the subunit composition of 5-HT3 receptors that are endogenous to neurones, and their regional expression within the central nervous system. We conclude by describing recent studies that have identified numerous HTR3A and HTR3B gene polymorphisms that impact upon 5-HT3 receptor function, or expression, and consider their relevance to (patho)physiology.

| S-EPMC6485434 | biostudies-literature

Structure activity relationship of brevenal hydrazide derivatives.

Project description:Brevenal is a ladder frame polyether produced by the dinoflagellate Karenia brevis. This organism is also responsible for the production of the neurotoxic compounds known as brevetoxins. Ingestion or inhalation of the brevetoxins leads to adverse effects such as gastrointestinal maladies and bronchoconstriction. Brevenal shows antagonistic behavior to the brevetoxins and shows beneficial attributes when administered alone. For example, in an asthmatic sheep model, brevenal has been shown to increase tracheal mucosal velocity, an attribute which has led to its development as a potential treatment for Cystic Fibrosis. The mechanism of action of brevenal is poorly understood and the exact binding site has not been elucidated. In an attempt to further understand the mechanism of action of brevenal and potentially develop a second generation drug candidate, a series of brevenal derivatives were prepared through modification of the aldehyde moiety. These derivatives include aliphatic, aromatic and heteroaromatic hydrazide derivatives. The brevenal derivatives were tested using in vitro synaptosome binding assays to determine the ability of the compounds to displace brevetoxin and brevenal from their native receptors. A sheep inhalation model was used to determine if instillation of the brevenal derivatives resulted in bronchoconstriction. Only small modifications were tolerated, with larger moieties leading to loss of affinity for the brevenal receptor and bronchoconstriction in the sheep model.

| S-EPMC4012454 | biostudies-literature

Structure-Activity Relationship of HER2 Receptor Targeting Peptide and Its Derivatives in Targeted Tumor Therapy.

Project description:Human epidermal growth factor (HER2) is a transmembrane tyrosine kinase receptor that is frequently overexpressed in breast cancer. Its increased level prognoses a poor patient outcome and a high mortality rate. Despite the widening spectrum of therapies that are becoming available to treat HER2+ breast cancer, its side effects and resistance still make this protein a valuable object of research in targeted tumor therapy. The role of tumor-targeting peptides has become more and more prominent in the last few decades due to their simple synthesis and pharmakokinetic properties. Here, we examine two fluorescently-labeled HER2-specific peptides and their combined analogues that are developed to target the extracellular region of HER2. The peptides are investigated on breast cancer cell lines with different HER2 expression profiles. Moreover, their extracellular localization and specificity are confirmed by flow cytometry and confocal microscopy. Therefore, a new, combined HER2 binding conjugate is obtained that interacts with HER2-overexpressing cells with high affinity and specificity. Furthermore, secondary structure prediction reveals that the α-helical content of the peptides is associated with their receptor recognition. This highly specific conjugate can be used as a starting point for diagnostical or drug-targeting purposes in upcoming studies.

| S-EPMC7072344 | biostudies-literature

Antitumor Activity of PEGylated and TEGylated Phenothiazine Derivatives: Structure-Activity Relationship.

Project description:The paper aims to investigate the antitumor activity of a series of phenothiazine derivatives in order to establish a structure-antitumor activity relationship. To this end, PEGylated and TEGylated phenothiazine have been functionalized with formyl units and further with sulfonamide units via dynamic imine bonds. Their antitumor activity was monitored in vitro against seven human tumors cell lines and a mouse one compared to a human normal cell line by MTS assay. In order to find the potential influence of different building blocks on antitumor activity, the antioxidant activity, the ability to inhibit farnesyltransferase and the capacity to bind amino acids relevant for tumor cell growth were investigated as well. It was established that different building blocks conferred different functionalities, inducing specific antitumor activity against the tumor cells.

| S-EPMC10049495 | biostudies-literature

Structure-Activity Relationships of Styrylquinoline and Styrylquinoxaline Derivatives as α-Synuclein Imaging Probes.

Project description:Synucleinopathies are characterized by the deposition of α-synuclein (α-syn) aggregates before the onset of clinical symptoms. Therefore, in vivo imaging of α-syn may contribute to early diagnosis of these diseases and has attracted much attention in recent years. However, no clinically useful probes have been reported. In the present study, 16 quinoline/quinoxaline derivatives with different styryl and fluorine groups were evaluated in order to develop α-syn imaging probes. Among them, SQ3, which is a quinoline analogue with a p-(dimethylamino)styryl group and fluoroethoxy group at the 2- and 7- positions of the skeleton, displayed moderate selectivity for α-syn aggregates over β-amyloid (Aβ) aggregates (K i = 230 nM), while maintaining high binding affinity for α-syn aggregates (K i = 39.3 nM). In a biodistribution study, [18F]SQ3 exhibited high uptake (2.08% ID/g at 2 min after intravenous injection) into a normal mouse brain. Taken together, we demonstrate that [18F]SQ3 has basic properties as a lead compound for the development of a useful α-syn imaging probe.

| S-EPMC9575165 | biostudies-literature

Anti-dengue-virus activity and structure-activity relationship studies of lycorine derivatives.

Project description:Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. No vaccines or specific therapeutics are currently available for dengue. Lycorine, which is a natural plant alkaloid, has been shown to possess antiviral activities against flaviviruses. In this study, a series of novel lycorine derivatives were synthesized and assayed for their inhibition of dengue virus (DENV) in cell cultures. Among the lycorine analogues, 1-acetyllycorine exhibited the most potent anti-DENV activity (EC50 =0.4 μM) with a reduced cytotoxicity (CC50 >300 μM), which resulted in a selectivity index (CC50 /EC50 ) of more than 750. The ketones 1-acetyl-2-oxolycorine (EC50 =1.8 μM) and 2-oxolycorine (EC50 =0.5 μM) also exhibited excellent antiviral activities with low cytotoxicity. Structure-activity relationships for the lycorine derivatives against DENV are discussed. A three-dimensional quantitative structure-activity relationship model was established by using a comparative molecular-field analysis protocol in order to rationalize the experimental results. Further modifications of the hydroxy group at the C1 position with retention of a ketone at the C2 position could potentially lead to inhibitors with improved overall properties.

| S-EPMC7162318 | biostudies-literature

Structure-Activity Relationship of NF023 Derivatives Binding to XIAP-BIR1.

Project description:Inhibitors of Apoptosis Proteins (IAPs) are conserved E3-ligases that ubiquitylate substrates to prevent apoptosis and activate the NF-kB survival pathway, often deregulated in cancer. IAPs-mediated regulation of NF-kB signaling is based on the formation of protein complexes by their type-I BIR domains. The XIAP-BIR1 domain dimerizes to bind two TAB1 monomers, leading to downstream NF-kB activation. Thus, impairment of XIAP-BIR1 dimerization could represent a novel strategy to hamper cell survival in cancer. To this aim, we previously reported NF023 as a potential inhibitor of XIAP-BIR1 dimerization. Here we present a thorough analysis of NF023 binding to XIAP-BIR1 through biochemical, biophysical and structural data. The results obtained indicate that XIAP-BIR1 dimerization interface is involved in NF023 binding, and that NF023 overall symmetry and the chemical features of its central moiety are essential for an efficient interaction with the protein. Such strategy provides original hints for the development of novel BIR1-specific compounds as pro-apoptotic agents.

| S-EPMC6460348 | biostudies-literature

Structure-Activity Relationship Study of 1<i>H</i>-Pyrrole-3-carbonitrile Derivatives as STING Receptor Agonists.

Project description:The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1H-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure-activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system. Representative compounds 7F, 7P, and 7R all displayed comparable activities to the reported STING agonist SR-717 in binding various hSTING alleles and induced reporter signal in human THP1 cell lines. Model compound 7F induced phosphorylation of TBK1, IRF3, p65, and STAT3 in a STING-dependent fashion and stimulated the expression of target genes IFNB1, CXCL10, and IL6 in a time-dependent manner in human THP1 cells. Our findings afforded a series of novel STING agonists with promising potential.

| S-EPMC10424313 | biostudies-literature

Structure activity relationship of 2-arylalkynyl-adenine derivatives as human A<sub>3</sub> adenosine receptor antagonists.

Project description:Recognition of nucleosides at adenosine receptors (ARs) is supported by multiple X-ray structures, but the structure of an adenine complex is unknown. We examined the selectivity of predicted A1AR and A3AR adenine antagonists that incorporated known agonist affinity-enhancing N 6 and C2 substituents. Adenines with A1AR-favoring N 6-alkyl, cycloalkyl and arylalkyl substitutions combined with an A3AR-favoring 2-((5-chlorothiophen-2-yl)ethynyl) group were human (h) A3AR-selective, e.g. MRS7497 17 (∼1000-fold over A1AR). In addition, binding selectivity over hA2AAR and hA2BAR and functional A3AR antagonism were demonstrated. 17 was subjected to computational docking and molecular dynamics simulation in a hA3AR homology model to predict interactions. The SAR of nucleoside AR agonists was not recapitulated in adenine AR antagonists, and modeling suggested an alternative, inverted binding mode with the key N2506.55 H-bonding to the adenine N 3 and N 9, instead of N 6 and N 7 as in adenosine agonists.

| S-EPMC6256369 | biostudies-literature

Synthesis and structure-activity relationship (SAR) studies of 1,2,3-triazole, amide, and ester-based benzothiazole derivatives as potential molecular probes for tau protein.

Project description:The pyridinyl-butadienyl-benzothiazole (PBB3 15) scaffold was used to develop tau ligands with improved in vitro and in vivo properties for imaging applications to provide insights into the etiology and characteristics of Alzheimer's disease. The photoisomerisable trans-butadiene bridge of PBB3 was replaced with 1,2,3-triazole, amide, and ester moieties and in vitro fluorescence staining studies revealed that triazole derivatives showed good visualisation of Aβ plaques, but failed to detect the neurofibrillary tangles (NFTs) in human brain sections. However, NFTs could be observed using the amide 110 and ester 129. Furthermore, the ligands showed low to high affinities (Ki = >1.5 mM-0.46 nM) at the shared binding site(s) with PBB3.

| S-EPMC10211319 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data