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The Journal of Pharmacology and... Sep 2005The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and...
The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and further vision loss. The balance between aqueous humor (AH) production and drainage determines IOP, and problems in AH outflow pathways are associated with open-angle glaucoma development. Previous studies have shown the presence of diadenosine tetraphosphate (Ap(4)A) and pentaphosphate (Ap(5)A) in the AH. Topic application of Ap(4)A to the cornea decreased IOP, whereas Ap(5)A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (Ap(n)As; n = 3-5) and Up(4)U (P(1),P(4)-(diuridine 5')-tetraphosphate; INS365) in outflow facility were tested. P2Y(1), P2Y(2), and P2Y(4) receptors were detected in TM cells by Western blot and immunocytochemistry. In TM cells, Ap(3)A, Ap(4)A, and Ap(5)A induced discrete intracellular calcium concentration ([Ca(2+)](i)) mobilizations compared with higher and more sustained [Ca(2+)](i) mobilizations after Up(4)U application. In bovine ocular anterior segments perfused at constant pressure, 1 microM Ap(3)A or Ap(4)A increased outflow facility, whereas Up(4)U or Ap(5)A did not modify it. 2-MeSADP, a selective P2Y(1) agonist, induced outflow facility increases similar to those obtained after Ap(3)A and Ap(4)A, and these were prevented by addition of the selective P2Y(1) receptor antagonist MRS-2179 (2'-deoxy-N(6)-methyladenosine-3',5'-diphosphate). Our results demonstrate that the hypotensive effect of Ap(4)A and other dinucleotides is mediated, at least in part, by increasing trabecular outflow facility through activation of P2Y(1) receptors. The latter would seem to be an interesting target in the development of antiglaucomatous drugs to selectively increase AH outflow.
Topics: Animals; Aqueous Humor; Calcium; Cattle; Cells, Cultured; Dinucleoside Phosphates; Intraocular Pressure; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Trabecular Meshwork
PubMed: 15947035
DOI: 10.1124/jpet.105.085274 -
Bioorganic & Medicinal Chemistry Letters Jun 2004A novel tandem synthetic-biosynthetic procedure is described for the synthesis of four new fluorescent dinucleoside polyphosphates: mant-Ap4A, mant-AppCH2ppA, TNP-Ap4A...
A novel tandem synthetic-biosynthetic procedure is described for the synthesis of four new fluorescent dinucleoside polyphosphates: mant-Ap4A, mant-AppCH2ppA, TNP-Ap4A and TNP-AppCH2ppA. These compounds are expected to supplement the existing etheno (epsilon) and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) labelled derivatives, being the fluorescent probes of choice to investigate polyphosphate/enzyme binding behaviour.
Topics: Boron Compounds; Dinucleoside Phosphates; Fluorescent Dyes; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Spectrum Analysis; Trinitrobenzenes; ortho-Aminobenzoates
PubMed: 15125938
DOI: 10.1016/j.bmcl.2004.03.060 -
Progress in Nucleic Acid Research and... 2003
Review
Topics: Base Pairing; Dinucleoside Phosphates; Hydrogen-Ion Concentration; Nucleic Acid Conformation; Oligonucleotides; Thermodynamics
PubMed: 14604016
DOI: 10.1016/s0079-6603(03)75009-0 -
Nucleic Acids Research Apr 1992In contrast to tetrazole, pyridine hydrochloride/imidazole converts nucleoside phosphoramidites to intermediates that show a high preference for phosphitilating hydroxyl...
In contrast to tetrazole, pyridine hydrochloride/imidazole converts nucleoside phosphoramidites to intermediates that show a high preference for phosphitilating hydroxyl groups relative to nucleoside amino groups. Use of this activating agent and incorporation of a pyridine hydrochloride/aniline wash step in the synthetic cycles permit synthesis of mixed base twenty-mer oligonucleotides from nucleoside reagents containing unprotected amino groups. This approach should be useful for the synthesis of oligonucleotide analogues containing substituents sensitive to reagents used in conventional deblocking steps. Pyridine hydrochloride itself is an effective reagent for activating nucleoside methylphosphonoamidites and ribonucleoside phosphoramidites, as well as deoxyribonucleoside phosphoramidites, when high O/N selectivety is not needed.
Topics: Base Sequence; Dinucleoside Phosphates; Molecular Sequence Data; Nucleosides; Oligodeoxyribonucleotides; Organophosphorus Compounds
PubMed: 1579488
DOI: 10.1093/nar/20.8.1879 -
Journal of Medicinal Chemistry Mar 2010Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and...
Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5',5''-P(1),P(4),alpha,beta-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5',5''-P(1),P(4),beta,gamma-methylene-tetraphosphate), 9, and di-(2-MeS)-adenosine-5',5''-P(1),P(3),alpha,beta-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y(1)R with EC(50) values of 0.42 and 0.46 microM, respectively, whereas analogue 10 had no activity. Analogues 8-10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37 degrees C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80-110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.
Topics: Alkaline Phosphatase; Animals; Blood Glucose; Cell Line, Tumor; Dinucleoside Phosphates; Dose-Response Relationship, Drug; Fasting; Humans; Insulin; Insulin Secretion; Male; Molecular Structure; Purinergic P2 Receptor Agonists; Rats; Rats, Wistar; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Serum; Structure-Activity Relationship
PubMed: 20175517
DOI: 10.1021/jm901621h -
Tetrahedron Letters 1991Symmetrical dinucleoside 5'-pyrophosphates have been synthesized from the corresponding nucleoside 5'-phosphate free acid in high yield. The one-pot procedure is carried...
Symmetrical dinucleoside 5'-pyrophosphates have been synthesized from the corresponding nucleoside 5'-phosphate free acid in high yield. The one-pot procedure is carried out in DMF or DMSO using triphenylphosphine and 2,2'-dipyridyldisulfide as the coupling agents, and 1-methylimidazole as the catalyst.
Topics: 2,2'-Dipyridyl; Chromatography, High Pressure Liquid; Dimethyl Sulfoxide; Dinucleoside Phosphates; Diphosphates; Disulfides; Imidazoles; Inosine Monophosphate; Organophosphorus Compounds
PubMed: 11538283
DOI: 10.1016/0040-4039(91)80754-t -
Journal of Medicinal Chemistry Jan 2012Dinucleoside polyphosphates, Np(n)N', exert their physiological effects via P2 receptors (P2Rs). Np(n)N' are attractive drug candidates as they offer better stability...
Dinucleoside polyphosphates, Np(n)N', exert their physiological effects via P2 receptors (P2Rs). Np(n)N' are attractive drug candidates as they offer better stability and specificity compared to nucleotides, the most common P2R ligands. To further improve the agonist properties of Np(n)N', we synthesized novel isosters of dinucleoside polyphosphates where N and N' are A or U and where the Pα or Pβ phosphate groups are replaced by boranophosphate, denoted as Np(n)(α-B)N' or Np(n)(β-B)N' (n = 3, 4), respectively. The potency of Np(n)(α/β-B)N' analogues was evaluated at tP2Y(1), hP2Y(2), hP2Y(4), and rP2Y(6) receptors. The most potent P2Y(1)R and P2Y(6)R agonists were the Up(4)(β-B)A (A isomer, EC(50) of 0.5 μM vs 0.004 μM for 2-SMe-ADP) and Up(3)(α-B)U (B isomer, EC(50) of 0.3 μM vs 0.2 μM for UDP), respectively. The receptor subtype selectivity is controlled by the position of the borano moiety on the Np(n)N' polyphosphate chain and the type of the nucleobase. In addition, Np(n)(α/β-B)N' proved ∼22-fold more resistant to hydrolysis by e-NPP1, as compared to the corresponding Np(n)N' analogues. In summary, Up(4)(β-B)A and Up(3)(α-B)U are potent, stable, and highly selective P2Y(1) and P2Y(6) receptor agonists, respectively.
Topics: Animals; Boranes; Calcium; Cell Line, Tumor; Dinucleoside Phosphates; Drug Stability; Humans; Hydrolysis; Models, Molecular; Molecular Conformation; Phosphoric Diester Hydrolases; Purinergic P2Y Receptor Agonists; Pyrophosphatases; Receptors, Purinergic P2Y; Stereoisomerism; Structure-Activity Relationship; Turkey
PubMed: 22107038
DOI: 10.1021/jm2013198 -
Wei Sheng Wu Xue Bao = Acta... Feb 2015Cyclic diadenosine monophosphate (c-di-AMP), a new second messenger found recently in bacteria, regulates various aspects of bacterial physiology, including cell growth,... (Review)
Review
Cyclic diadenosine monophosphate (c-di-AMP), a new second messenger found recently in bacteria, regulates various aspects of bacterial physiology, including cell growth, cell wall homeostasis and virulence. In addition to its functions in bacterial physiology, c-di-AMP represents a putative bacterial secondary signaling molecule sensed by eukaryotic host cells and triggers innate immunity. The level of c-di-AMP in bacteria is regulated by the activities of diadenylate cyclase (DAC) and phosphodiesterases (PDE) , the former harbors a DisA_N domain, and the latter a DHH or DHH/DHHA1 domain. This review gives an overview on metabolic pathway, regulatory mechanism, receptor proteins and biological function of c-di-AMP in bacteria, as well as its application and trends of development.
Topics: Adenosine Monophosphate; Bacteria; Bacterial Proteins; Dinucleoside Phosphates; Second Messenger Systems
PubMed: 25958691
DOI: No ID Found -
Journal of Medicinal Chemistry Feb 2008Platelet P2Y12 receptors play a central role in the regulation of platelet function and inhibition of this receptor by treatment with drugs such as clopidogrel results...
Platelet P2Y12 receptors play a central role in the regulation of platelet function and inhibition of this receptor by treatment with drugs such as clopidogrel results in a reduction of atherothrombotic events. We discovered that modification of natural and synthetic dinucleoside polyphosphates and nucleotides with lipophilic substituents on the ribose and base conferred P2Y12 receptor antagonist properties to these molecules producing potent inhibitors of ADP-mediated platelet aggregation. We describe methods for the preparation of these functionalized dinucleoside polyphosphates and nucleotides and report their associated activities. By analysis of these results and by deconstruction of the necessary structural elements through selected syntheses, we prepared a series of highly functionalized nucleotides, resulting in the selection of an adenosine monophosphate derivative (62) for further clinical development.
Topics: Adenosine Monophosphate; Blood Platelets; Calcium; Cell Line, Tumor; Dinucleoside Phosphates; Humans; In Vitro Techniques; Membrane Proteins; Nucleotides; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Structure-Activity Relationship
PubMed: 18232657
DOI: 10.1021/jm701348d -
Journal of Biomolecular Structure &... 2022Human stimulator of interferon genes (STING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic...
Human stimulator of interferon genes (STING) is a signaling adaptor protein that triggers innate immune system by response to cytosolic DNA and second messenger cyclic dinucleotides (CDNs). Natural CDNs contain purine nucleobase with different phosphodiester linkage types (3'-3', 2'-2' or mixed 2'-3'-linkages) and exhibit different binding affinity towards STING, ranging from micromolar to nanomolar. High-affinity CDNs are considered as suitable candidates for treatment of chronic hepatitis B and cancer. We have used molecular dynamics simulations to investigate dynamical aspects of binding of natural CDNs (specifically, 2'-2'-cGAMP, 2'-3'-cGAMP, 3'-3'-cGAMP, 3'-3'-c-di-AMP, and 3'-3'-c-di-GMP) with STING protein. Our results revealed that CDN/STING interactions are controlled by the balance between fluctuations (conformational changes) in the CDN ligand and the protein dynamics. Binding of different CDNs induces different degrees of conformational/dynamics changes in STING ligand binding cavity, especially in α-helices, the so-called lid region and α-tails. The ligand residence time in STING protein pocket depends on different contribution of R232 and R238 residues interacting with oxygen atoms of phosphodiester groups in ligand, water distribution around interacting charged centers (in protein residues and ligand) and structural stability of closed conformation state of STING protein. These findings may perhaps guide design of new compounds modulating STING activity.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Molecular Dynamics Simulation; Ligands; Dinucleoside Phosphates; DNA; Oligonucleotides
PubMed: 34187319
DOI: 10.1080/07391102.2021.1942213