1,721,132 research outputs found
Therapeutic potential of A2 and A3 adenosine receptor: a review of novel patented ligands.
No full textIntroduction: Adenosine exerts its effects by interacting with G-protein coupled receptors (GPCR) namely A1, A2A, A2B and A3, respectively. These are involved in several diseases, for example and most importantly, Parkinson’s disease, ischemia and inflammation. There is high interest in the development of potent and selective ligands for these adenosine receptor (AR) subtypes, primarily for their therapeutic potential but also as pharmacological tools in receptor studies.
Areas covered: This paper concentrates on reviewing the therapeutic potential of A2 and A3 ARs, which represent the most interesting subtypes of recent years. A general description of each receptor is reported with novel agonist and antagonist structures, patented in 2008 -- 2011. PubMed and Free Patents Online databases were principally used to collect all the material.
Expert opinion: In the past years, by modulating A2 and A3ARs, several new possible therapeutic applications were discovered. For this reason, research concerning AR ligands is still of great interest. In particular, few potent and selective A2B agonists and antagonists are actually reported and a clear SAR (structure--activity relationship) profile lacks for this AR subtype. At the A3AR, allosteric modulation may prevent problems related to the high difference between rat and human orthosteric sites and simplify the preclinical studies on A3AR
Tecniques: recent developments in computer aided engineering of GPCR ligands using the human A3 adenosine 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 O40% 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
Anticonvulsivanti
No full textL’epilessia è una sindrome neurologica caratterizzata da crisi epilettiche ricorrenti e imprevedibili. Nel mondo ne sono colpite 50 milioni di persone, l’80% delle quali proviene da paesi in via di sviluppo. Il termine crisi epilettica indica un’alterazione transitoria dell’attività cerebrale causata da scariche neuronali anomale, eccessive e sincrone, che colpiscono intere popolazioni di neuroni. Queste scariche possono causare piccoli movimenti involontari, forti convulsioni, alterazioni psichiche, perdita dell’attenzione e addirittura alterare lo stato di coscienza. Una crisi può essere definita non epilettica quando provocata in un cervello normale tramite elettroshock o sostanze convulsivanti. Le diverse tipologie di crisi epilettiche possono essere classificate, secondo i sintomi clinici e il tracciato EEG (elettroencefalogramma), in crisi parziali e generalizzate. Le crisi parziali originano da un punto preciso (focale) di uno degli emisferi cerebrali, mentre le crisi generalizzate coinvolgono l’intero cervello e non è possibile localizzare un’origine precisa dell’impulso. Benché si possano distinguere epilessie di tipo idiopatico ed epilessie di tipo sintomatico (causate da lesioni come trauma o infarto cerebrale), l’eziologia di tali sindromi rimane ignota. Per tale motivo i farmaci attualmente a disposizione sono anticonvulsivanti, cioè contrastano il sintomo, la crisi epilettica (le convulsioni), ma non prevengono o curano l’epilessia. I farmaci anticonvulsivanti in uso riescono a controllare le crisi nel 70-80% dei pazienti, mentre falliscono nel restante 20-30% dei casi
Advances in Computational Techniques to Study GPCR-Ligand Recognition
Full text linkG-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
A 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
A3 Adenosine receptor antagonistsdelay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro
No full textThe role of adenosine A3 receptor activation during ischaemia-like conditions produced byoxy gen and glucose deprivation (OGD) was evaluated with extracellular recordings from the CA1 region of rat hippocampal slices. In all, 7 min of OGD evoked tissue anoxic depolarisation (AD, peak atB7 min from OGD start, n1⁄420) and were invariablyfollowed byirreversible loss of electrically evoked field epsps (fepsps, n1⁄442)
Response surface analysis as alternative 3D-QSAR tool: human A3 adenosine receptor antagonists as a key study.
No full textG protein-coupled receptors as challenging druggable targets: insights from in silico studies
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