ABSTRACT
Piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-quinolin-4-ones have been identified with high binding affinities for 5-HT(6) receptor. In particular, 2-methyl-5-(N-methyl-piperazin-1-yl)-1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (8g) exhibits high binding affinity toward 5-HT(6) (IC(50)=8nM) receptor with good selectivity over other serotonin and dopamine receptors.
Subject(s)
Quinolones/chemistry , Quinolones/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Animals , Cell Line , Humans , Ligands , Models, Molecular , Protein Binding , Structure-Activity RelationshipABSTRACT
(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT(2C) and 5-HT(6) receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT(2C) (IC(50)=4 nM) and 5-HT(6) receptors (IC(50)=3 nM) with good selectivity over other serotonin (5-HT(1A), 5-HT(2A), and 5-HT(7)) and dopamine (D(2)-D(4)) receptor subtypes. In 5-HT(2C) and 5-HT(6) receptor functional assays, this compound showed considerable antagonistic activity for both receptors.
Subject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Antipsychotic Agents/chemical synthesis , Piperazines/chemistry , Receptors, Serotonin/classification , Receptors, Serotonin/drug effects , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
Picornaviruses (PV) and coronaviruses (CoV) are positive-stranded RNA viruses which infect millions of people worldwide each year, resulting in a wide range of clinical outcomes. As reported in this study, using high throughput screening against approximately 6800 small molecules, we have identified several novel inhibitors of SARS-CoV 3CL(pro) with IC(50) of low microM. Interestingly, one of them equally inhibited both 3C(pro) and 3CL(pro) from PV and CoV, respectively. Using computer modeling, the structural features of these compounds as individual and common protease inhibitors were elucidated to enhance our knowledge for developing anti-viral agents against PV and CoV.
Subject(s)
Coronavirus/drug effects , Coronavirus/enzymology , Peptide Hydrolases/metabolism , Picornaviridae/drug effects , Picornaviridae/enzymology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amino Acid Sequence , Computer Simulation , Conserved Sequence , Drug Evaluation, Preclinical , Models, Molecular , Molecular Sequence Data , Peptide Hydrolases/chemistry , Protein Binding , Protein Structure, Tertiary , Sequence Alignment , Structure-Activity RelationshipABSTRACT
A novel series of 1H-indole-3-carboxylic acid pyridine-3-ylamides were synthesized and identified to show high affinity and selectivity for 5-HT(2C) receptor. Among them, 1H-indole-3-carboxylic acid[6-(2-chloro-pyridin-3-yloxy)-pyridin-3-yl]-amide (15k) exhibits the highest affinity (IC(50)=0.5 nM) with an excellent selectivity (>2000 times) over other serotonin (5-HT(1A), 5-HT(2A), and 5-HT(6)) and dopamine (D(2)-D(4)) receptors.
Subject(s)
Amines/chemical synthesis , Indoles/chemical synthesis , Pyridines/chemical synthesis , Serotonin 5-HT2 Receptor Antagonists , Amines/chemistry , Animals , CHO Cells , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Cricetinae , Cricetulus , Drug Design , Humans , Indoles/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Pyridines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Technology, Pharmaceutical/methodsABSTRACT
A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT(6) antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT(6) receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (K(i)=12.3 nM) for 5-HT(6) receptor with good selectivity over other serotonin and dopamine (D(1)-D(4)) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC(50)=0.61 microM).
Subject(s)
Quinolines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Cell Line , Humans , Quinolines/chemistry , Radioligand Assay , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/metabolismABSTRACT
A series of polyguanidylated dendritic structures that can be used as molecular translocators have been designed and synthesized based on nonpeptide units. The dendritic oligoguanidines conjugated with fluorescein or with a green fluorescent protein (GFP) mutant as cargos were isolated and characterized. Quantification and time-course analyses of the cellular uptake of the conjugates using HeLa S3 and human cervical carcinoma cells reveal that the polyguanidylated dendrimers have comparable translocation efficiency to the Tat(49-57) peptide. Furthermore, the deconvolution microscopy image analysis shows that they are located inside the cells. These results clearly show that nonlinear, branched dendritic oligoguanidines are capable of translocation through the cell membrane. This work also demonstrates the potential of these nonpeptidic dendritic oligoguanidines as carriers for intracellular delivery of small molecule drugs, bioactive peptides, and proteins.
Subject(s)
Cell Membrane/metabolism , Guanidines/chemistry , Guanidines/metabolism , Biopolymers/chemistry , Biopolymers/metabolism , Fluorescein/chemistry , Green Fluorescent Proteins , HeLa Cells , Humans , Luminescent Proteins/metabolism , Microscopy, Fluorescence , Protein TransportABSTRACT
4-Hydroxyphenylacetic acid amides and 4-hydroxycinnamamides were synthesized and their antioxidant and neuroprotective activities were evaluated. Among the prepared compounds, 8b, and exhibited potent inhibition of lipid peroxidation in rat brain homogenates, and marked DPPH radical scavenging activities. Furthermore, and exhibited neuroprotective action against the oxidative damage induced by the exposure of primary cultured rat cortical cells to H(2)O(2), xanthine/xanthine oxidase, or Fe(2+)/ascorbic acid. Based on these results, we found that was the most potent antioxidant among the compounds tested.
