1,721,120 research outputs found
Non peptidic alpha(V)beta(3) antagonists: Recent developments
No full textThe alphavbeta3 receptor, which are members of the group of the cellular adhesion
molecules (CAM), are heterodimeric transmembrane glycoprotein receptors involved
in processes such as cell-cell and cell-matrix adhesion, cell migration and
signaling. Integrin alphavbeta3 receptor is expressed on almost all cells
originating from the mesenchyme and seem to mediate several biological processes,
including adhesion of osteoblasts to the bone matrix, migration of vascular
smooth muscle cells, and angiogenesis. Many efforts were done in the last 10
years to individuate inhibitors for alphavbeta3 receptors, due to their
involvement in important pathophysiological functions. In fact, selective
alphavbeta3 antagonists offer new therapeutic opportunities for the treatment of
several human pathologies like osteoporosis, restenosis and diseases involving
neovascularization such as rheumatoid arthritis, tumor induced angiogenesis and
metastasis. Purpose of this account is to summarize the recent developments in
the field of non-peptidic alphavbetav antagonists
Functionalized ligands targeting G protein-coupled adenosine receptors
No full textAdenosine receptors are G protein-coupled receptors involved in important physio-pathological conditions. For this reason, from their discovery, the research of potent and selective ligands attracted the interest of researchers working in the field. Beyond the classical agonists, antagonists or allosteric ligands, several efforts were made in the development of functionalized ligands for the adenosine receptors. Functionalized ligands are molecules were an adenosine receptor ligand is conjugated to a moiety which confers new features to the molecule, such as additional therapeutic effect or target selectivity, receptor probing, improved pharmacokinetic profile, etc. In this commentary, an overview on the applications of functionalized ligands for the adenosine receptor was presented, even if most of the concepts are applicable to all G protein-coupled receptors
Techniques: Recent developments in computer-aided engineering of GPCR ligands using the human adenosine A(3) receptor as an example
No full textG-protein-coupled receptors (GPCRs) represent the largest known family of signal-transducing molecules, and convey signals for light and many extracellular regulatory molecules. GPCRs are dysfunctional or dysregulated in several human diseases and are estimated to be the targets of >40% of the drugs used in clinical medicine today. The crystal structure of rhodopsin provides the first information on the three-dimensional structure of GPCRs, which now supports homology modeling studies and structure-based drug-design approaches. In this article, we review recent work on adenosine receptors, a family of GPCRs, and, in particular, on adenosine A(3) receptor antagonists. We focus on an iterative, bi-directional approach in which models are used to generate hypotheses that are tested by experimentation; the experimental findings are, in turn, used to refine the model. The success of this approach is due to the synergistic interaction between theory and experimentation
Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat cells, a human leukemia line.
No full textAdenosine modulates various physiological effects on many cell types by activating four different subtypes of G protein coupled receptors classified as A1, A2A, A2B and A3. Recently, 5-N-(4-methoxyphenyl-carbamoyl)amino-8-propyl-2-(2-furyl)-pyrazolo-[4,3-e]1,2,4-triazolo[1,5-c]-pyrimidine, [3H]MRE3008F20, has been identified as a potent and selective radiolabelled antagonist of human recombinant A3 receptors (1). In this study we investigated the pharmacological and biochemical profile of A3 subtypes in Jurkat T cells, a human leukemia line, where the presence of A2B and A2A but not A3 receptors has been previously demonstrated. A3 receptors were first revealed by RT-PCR experiments; then saturation of [3H]MRE3008F20 binding to A3 receptors (range 0.2-2nM) showed a single high affinity binding site with Kd of 1.90.2 nM and Bmax of 1.30.1 pmol/mg of protein. Competition studies of [3H]MRE3008F20 binding (2nM) using typical adenosine ligands displayed a pharmacological profile typical of the A3 subtype. Agonist competition curves yelded both a high (30%) and a low-affinity state of A3 receptors. Cl-IB-MECA and IB-MECA were the most potent compounds with KH of 1.6, 2.7 nM and KL of 83, 150 nM, respectively. Functional studies showed that Cl-IBMECA and IB-MECA, were able to inhibit cAMP accumulations with EC50 values of 3.50.3 and 120.1 nM, respectively. The same agonists (30 M) stimulated Ca2+ release from intracellular Ca2+ pools from a basal level of 100-150 nM to a stimulated level of 250-300 nM. Finally, A3 agonists (30-40M) and antagonists (1-10M) produced a cell death effect, reducing cell number to 40% of control (p<0.05, ANOVA and Dunnett’s test) as demonstrated by different viability assays: trypan blue, JAM and MTT assays. These data are the first evidence of the presence of functional A3 adenosine receptors in Jurkat cells.
1. Varani K., Merighi S., Gessi S., Klotz K.N., Leung E., Baraldi P.G., Cacciari B., Romagnoli R., Spalluto G., and Borea P.A. (2000) Mol. Pharmacol. 57:968-975
1H-pyrazolo[2,3-d][1,2,4]triazine-3,7-diones as a new class of human leukocyte elastase inhibitors
No full textA novel series of 1H-2-phenyl-substituted-pyrazolo[2,3-d][1,2,4]triazine-3,7-diones (3a-g) as potential inhibitors of Human Leukocyte Elastase (HLE) are reported, the acyl-pyrazole being probably involved in the inhibition mechanism of the serino-protease enzymes. The most potent inhibitor both in vivo and in vitro was 2-o-methoxyphenyl-5-methyl-6-nitro-pyrazolo[2,3-d][1,2,4]triazine-3,7-dione, which significantly suppressed the HLE-induced pulmonary injury in rats when administered orally (100 mg/kg, 3 h prior to HLE administration)
G protein-coupled receptors as challenging druggable targets: insights from in silico studies
No full textA facile and versatile route to the synthesis of fused 2-pyridones: Useful intermediates for policyclic systems
No full textThe reaction of various heteroarom. amino nitriles with di-Et malonate under basic conditions is reported. This reaction affords a series of different highly functionalized 2-pyridone condensed systems, which can be suitable intermediates in the construction of polyheterocyclic structures
DNA minor groove alkylating agents structurally related to distamycin A
No full textA review with 39 refs. Analogs of naturally occurring antitumor agents, such us distamycin A, which bind in the minor groove of DNA, represent a new class of antineoplastic compds. currently under investigation. Distamycin A has attracted researchers attention not only for its biol. activity, but also for its non-intercalative binding to the minor groove of double-stranded B-DNA, where it forms a strong reversible complex preferentially at the nucleotide sequences consisting of 4 - 5 adjacent AT base pairs. Distamycin has also been used as a DNA sequence-selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase in cytotoxicity, in comparison to that of distamycin alone. In the last few years, several hybrid compds., in which known antitumor derivs. or simple active moieties of known antitumor agents have been tethered to distamycin frames, have been designed, synthesized and tested. Several efforts have been made to modify the DNA sequence selectivity and stability of distamycin; structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles resulting in a novel class of minor groove binding mols. called lexitropsins. The role of the amidino moiety has also been studied by substitution with various groups, including ionizable, acid or basic and non-ionizable groups. The synthesis of a hybrid derived from combining distamycin A and a naturally occurring alkylating agent structurally related to pyrrolo [2,1-c][1,4] benzodiazepine group, such as anthramycin and DC-81, has been also reported. Several classes of distamycin derivs. that have been reported in the published literature and in recent patent fillings have been described in this review article
Advances in Computational Techniques to Study GPCR-Ligand Recognition
No full textG-protein-coupled receptors (GPCRs) are among the most intensely investigated drug targets. The recent revolutions in protein engineering and molecular modeling algorithms have overturned the research paradigm in the GPCR field. While the numerous ligand-bound X-ray structures determined have provided invaluable insights into GPCR structure and function, the development of algorithms exploiting graphics processing units (GPUs) has made the simulation of GPCRs in explicit lipid-water environments feasible within reasonable computation times. In this review we present a survey of the recent advances in structure-based drug design approaches with a particular emphasis on the elucidation of the ligand recognition process in class A GPCRs by means of membrane molecular dynamics (MD) simulations
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