1,721,064 research outputs found
Identification of a specific residue that confers BzATP sensitivity to P2X2 receptors
No full textP2X receptors (P2XR) are trimeric ATP-gated cation channels involved in the fast signal transduction in many cells. Significant advances in the molecular understanding of the P2XR function that have been achieved by the availability of high-resolution structures of the zfP2X4R and, recently, hP2X3R and pdP2X7R [1-4]. However, little is known regarding the molecular determinants of the subtype specific potency and efficacy of orthostericP2XR ligands. We used docking analyses performed athomology models of the rP2X2R and rP2X7R [5,6] to analyze the ligand-binding of ATP and the potent P2X7R agonist 2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate (BzATP) that is a weak and partial agonist at the P2X2R. The difference between ATP and BzATP is the 4-benzoylbenzoyl (Bz) moiety present at the ribose of the nucleotide in BzATP. We identified two residues K212 and S284 of the P2X2R that spatially correspond to the P2X7R-specific aromatic residues F218 and F288of the dorsal fin and left flipper domains, respectively. Residues at these positions may coordinate the ribose and Bz moiety of ATP and BzATP, respectively, and determine the different potencies of these ligands at the P2X2R. The K212 and S284 of the P2X2R were substituted by phenylalanine residues to yield rP2X2 RK212F and rP2X2RS284F and were analyzed by TEVC electrophysiology following expression in X. laevis oocytes. Mutating S284 to F in rP2X2Rdid not affect the potency for ATP or BzATP. By contrast, the introduction of an aromatic moiety in position 212 as realized in the P2X2RK212F mutant significantly reduced and strongly increased the potency for ATP and BzATP, respectively. BzATP exhibited a higher potency and efficacy than ATP at the rP2X2RK212F. Our results clearly indicate that an aromatic moiety facing the water-exposed surface in the α3-helix of the P2X2R determines BzATP potency and efficacy, but weakensthe potency and efficacy of ATP
Emerging Roles of Purinergic Signaling in Diabetes
Full text linkPurinergic signaling accounts for a complex network of receptors and extracellular enzymes responsible for the generation, recognition and degradation of extracellular ATP and adenosine. The main actors of this system include P2X, P2Y and Adenosine Receptors, ectonucleotidases CD39 and CD73 and Adenosine Deaminase. The purinergic network recently emerged as a central player in several physiopathological conditions particularly those linked to immune system regulation including type 1 and type 2 diabetes
P2X7 Receptor as a Therapeutic Target
No full textP2X7 receptor is an ATP-gated cation channel that upon agonist interaction leads to cellular influx of Na+ and Ca2 + and efflux of K+. P2X7 is expressed by a wide variety of cells and its activation mediates a large number of biological processes like inflammation, neuromodulation, cell death or cell proliferation and it has been associated to related pathological conditions including infectious, inflammatory, autoimmune, neurological, and musculoskeletal disorders and, in the last years, to cancer. This chapter describes structural features of P2X7, chemical properties of its agonist, antagonist, and allosteric modulators and summarizes recent advances on P2X7 receptor as therapeutic target in the aforementioned diseases. We also give an overview on recent literature suggesting that P2X7 single-nucleotide polymorphisms could be exploited as diagnostic biomarkers for the development of tailored therapies
N6-methoxy-2-alkynyladenosine derivatives as highly potent and selective ligands at the human A(3) adenosine receptor
No full textA new series of N6-methoxy-2-(ar)alkynyladenosine derivatives has been synthesized and tested at the human recombinant adenosine receptors. Binding studies demonstrated that the new compounds possess high affinity and selectivity for the A3 subtype. Among them, compounds bearing an N-methylcarboxamido substituent in the 4¢-position showed the highest A3 affinity and selectivity. In particular, the N6-methoxy-2-pacetylphenylethynylMECA
(40; Ki A3 ) 2.5 nM, A3 selectivity versus A1 ) 21 500 and A2A ) 4200) results
in one of the most potent and selective agonists at the human A3 adenosine receptor reported so far.
Furthermore, functional assay, performed with selected new compounds, revealed that the presence of an
alkylcarboxamido group in the 4¢-position seems to be essential to obtain full agonists at the A3 subtype.
Finally, results of molecular docking analysis were in agreement with binding and functional data and could
explain the high affinity and potency of the new compounds
Design, synthesis, and biological evaluation of new mitonafide derivatives as potential antitumor drugs
No full textA series of potential DNA-binding antitumor agents, 2-[omega-(alkylamino) alkyl]-6-{[omega-(alkylamino) alkyl] amino}-1H-benzo[de] isoquinolin-1,3(2H)-diones and 1,7-bis{6-[(omega-(dimethylamino) alkyl) amino]-1,3dioxo-1H-benzo[de] isoquinolin-2(3H)-yl}-4-methyl-4-azaheptanes, have been prepared as mitonafide derivatives. Their DNA-binding ability and cytotoxic activity have been evaluated. Some of the target compounds have shown high DNA affinity as well as relevant cytotoxic properties. (C) 2008 Elsevier Ltd. All rights reserved
Synthesis and biological activity of trisubstituted adenines as A(2A) adenosine receptor antagonists
No full textThe discovery of new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease, has become an attractive field of research. Due to the regulation of D2 receptor activity by A2 A adenosine receptor, potent and selective ligands of A2 A subtype could be useful tools to study neurodegenerative disorders. A series of 2,8-disubstituted-9-ethyladenine derivatives was synthesized and tested in binding affinity assay at human adenosine receptors. New compounds showed good affinity and selectivity at A2 A receptor versus the other subtypes. The introduction of a bromine atom in 8-position increased the affinity of these compounds, leading to ligands with Ki in the nanomolar range
A patent review of adenosine A2B receptor antagonists (2016-present)
No full textIntroduction A(2B) adenosine receptor (A(2B)AR) plays a crucial role in pathophysiologic conditions associated with high adenosine release, typical of airway inflammatory pathologies, gastrointestinal disorders, cancer, asthma, type 2 diabetes, and atherosclerosis. In some pathologies, simultaneous inactivation of A(2A) and A(2B)ARs is desirable to have a synergism of action that leads to a greater efficacy of the pharmacological treatment and less side effects due to the dose of drug administered. In this context, it is strongly required to identify molecules capable of selectively antagonizing A(2B)AR or A(2A)/A(2B)ARs. Areas covered The review provides a summary of patents, published from 2016 to present, on chemicals and their clinical use. In this paper, information on the biological activity of representative structures of recently developed A(2B) or A(2A)/A(2B) receptor ligands is reported. Expert opinion Among the four P1 receptors, A(2B)AR is the most inscrutable and the least studied until a few years ago, but its involvement in various inflammatory pathologies has recently made it a pharmacological target of high interest. Many efforts by the academy and pharmaceutical companies have been made to discover potential A(2B)AR and A(2A)/A(2B)ARs drugs. Although several compounds have been synthesized only a few molecules have entered clinical trials
A(2A) Adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists
No full textSince the discovery of the biological effects of adenosine, the development of potent and selective agonists and antagonists of
adenosine receptors has been the subject of medicinal chemistry research for several decades, even if their clinical evaluation has been
discontinued. Main problems include side effects due to the ubiquity of the receptors and the possibility of side effects, or to low brain
penetration (in particular for the targeting of CNS diseases), short half-life of compounds, lack of effects. Furthermore, species differences in the affinity of ligands make difficult preclinical testing in animal models. Nevertheless, adenosine receptors continue to represent promising drug targets. A2A receptor has proved to be a promising pharmacological target for small synthetic ligands, and while A2A agonists are undergoing clinical trials for myocardial perfusion imaging and as anti-inflammatory agents, A2A antagonists represent an attractive field of research to discover new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease. Furthermore, the information coming from bioinformatics and molecular modeling studies for the A2A receptor has made easier the understanding of ligand-target interaction and the rational design of agonists and antagonists for this subtype. The aim of this review is to show an overview of the most significant steps and progresses in developing A2A adenosine receptor agonists and antagonists
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