ABSTRACT
Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.
Subject(s)
Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Drug Design , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Dopamine D3/metabolism , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/classification , Binding Sites , Drug Evaluation, Preclinical , Humans , Ligands , Mice , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
The new germacrane derivatives ketopelenolides C and D have been isolated from great mugwort (Artemisia arborescens). Their stereostructure elucidation exemplifies some of the most common pitfalls facing the configurational assignment of medium-sized polyfunctionalized compounds. It was established through a combined strategy including chemical derivatization, NMR data analysis, molecular modeling, and quantum-mechanical calculations including a comparison between experimental 13C NMR data and a Boltzmann-weighted average of DFT-calculated 13C NMR chemical shifts.
Subject(s)
Artemisia/chemistry , Sesquiterpenes, Germacrane/chemistry , Sesquiterpenes, Germacrane/isolation & purification , Computer Simulation , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , StereoisomerismABSTRACT
Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
Subject(s)
Acetylcholinesterase/chemistry , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Models, Molecular , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Binding Sites , Computational Biology , Crystallography, X-Ray , Drug Design , Humans , Protein Conformation , Structure-Activity Relationship , Tacrine/chemistryABSTRACT
We report on the construction, production, and characterization of a new fully human dimeric immunoRNase, obtained by fusion of Erbicin, a human anti-ErbB2 single-chain antibody fragment (scFv), with a dimeric mutant of human pancreatic RNase (HHP2-RNase). This novel immunoagent with 2 scFv moieties each fused to 1 of the 2 subunits of the dimeric RNase, called ERB-HHP2-RNase, has shown improved biologic properties with respect to the previously reported monomeric ERB-hRNase immunoRNase: it selectively binds ErbB2-positive cancer cells with an increased avidity; it is not inhibited by the cytosolic ribonuclease inhibitor; it is endowed with a more powerful cytotoxic activity.
Subject(s)
Neoplasms/immunology , Neoplasms/therapy , Ribonucleases/immunology , Ribonucleases/metabolism , Cell Line, Tumor , Dimerization , Gene Expression , Humans , Immunoglobulin Variable Region/immunology , Immunotherapy , Neoplasms/enzymology , Pancreas/enzymology , Receptor, ErbB-2/immunology , Ribonucleases/genetics , Ribonucleases/isolation & purificationABSTRACT
A new series of diterpenes, the jatrophanes euphoscopin M (1), euphoscopin N (2) and euphornin L (3), and the lathyrane euphohelioscopin C (7) were isolated from plants of Euphorbia helioscopia L., together with four other known analogues, euphoscopin C (4), euphornin (5), epieuphoscopin B (6) and euphohelioscopin A (8). The new compound stereostructures were elucidated by NMR analysis and computational data. The resulting isolated diterpenes were found to be potent inhibitors of P-glycoprotein (ABCB1), while showing an absence of significant activity against BCRP (ABCG2), despite the high substrate overlapping of these transporters, thus including them in the third-generation class of specific multidrug transporter modulators.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , Diterpenes/chemistry , Animals , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Molecular Structure , NIH 3T3 Cells , StereoisomerismABSTRACT
Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed.
Subject(s)
Acridines/chemical synthesis , Antimalarials/chemical synthesis , Hydrazones/chemical synthesis , Quinolines/chemical synthesis , Acridines/chemistry , Acridines/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/pharmacology , Drug Design , Drug Resistance , Hemeproteins/antagonists & inhibitors , Humans , Hydrazones/chemistry , Hydrazones/pharmacology , KB Cells , Malaria/drug therapy , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Conformation , Parasitic Sensitivity Tests , Plasmodium berghei , Plasmodium falciparum/drug effects , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
We describe herein the development of novel huperzine A-tacrine hybrids characterized by 3-methylbicyclo[3.3.1]non-3-ene scaffolds. These compounds were specifically designed to establish tight interactions, through different binding modes, with the midgorge recognition sites of human acetylcholinesterase (hAChE: Y72, D74) and human butyrylcholinesterase (hBuChE: N68, D70) and their catalytic or peripheral sites. Compounds 5a-c show a markedly improved biological profile relative to tacrine and huperzine A.
