NED-19

Last updated
NED-19
NED-19 structure.png
Identifiers
  • (1R,3S)-1-[3-[[4-(2-fluorophenyl)piperazin-1-yl]methyl]-4-methoxyphenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid
CAS Number
PubChem CID
ChemSpider
ChEBI
ChEMBL
Chemical and physical data
Formula C30H31FN4O3
Molar mass 514.601 g·mol−1
3D model (JSmol)
  • COC1=C(C=C(C=C1)[C@@H]2C3=C(C[C@H](N2)C(=O)O)C4=CC=CC=C4N3)CN5CCN(CC5)C6=CC=CC=C6F
  • InChI=1S/C30H31FN4O3/c1-38-27-11-10-19(16-20(27)18-34-12-14-35(15-13-34)26-9-5-3-7-23(26)31)28-29-22(17-25(33-28)30(36)37)21-6-2-4-8-24(21)32-29/h2-11,16,25,28,32-33H,12-15,17-18H2,1H3,(H,36,37)/t25-,28+/m0/s1
  • Key:FUHCEERDBRGPQZ-LBNVMWSVSA-N

Trans-NED-19 is a drug which acts as a potent and selective antagonist of the endogenous calcium channel opener nicotinic acid adenine dinucleotide phosphate (NAADP), thereby reducing the normal NAADP-mediated calcium flux without blocking calcium channels directly. It is used in research into the functions of NAADP signalling inside many different cell types. [1] [2] [3] [4] [5] [6] [7] [8]

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.

Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

<span class="mw-page-title-main">Cyclophilin</span>

Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin, an immunosuppressant which is usually used to suppress rejection after internal organ transplants. They are found in all domains of life. These proteins have peptidyl prolyl isomerase activity, which catalyzes the isomerization of peptide bonds from trans form to cis form at proline residues and facilitates protein folding.

<span class="mw-page-title-main">Calcium signaling</span> Intracellular communication process

Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.

<span class="mw-page-title-main">CD38</span> Protein-coding gene in the species Homo sapiens

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.

<span class="mw-page-title-main">TRPV6</span> Protein-coding gene in the species Homo sapiens

TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

<span class="mw-page-title-main">Cyclic ADP-ribose</span> Chemical compound

Cyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the adenosine (like ADP), further connected to another ribose at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 (N1) of the same adenine base (whose position N9 has the glycosidic bond to the other ribose). The N1-glycosidic bond to adenine is what distinguishes cADPR from ADP-ribose (ADPR), the non-cyclic analog. cADPR is produced from nicotinamide adenine dinucleotide (NAD+) by ADP-ribosyl cyclases (EC 3.2.2.5) as part of a second messenger system.

<span class="mw-page-title-main">Nicotinic acid adenine dinucleotide phosphate</span> Chemical compound

Nicotinic acid adenine dinucleotide phosphate, (NAADP), is a Ca2+-mobilizing second messenger synthesised in response to extracellular stimuli. Like its mechanistic cousins, IP3 and cyclic adenosine diphosphoribose (Cyclic ADP-ribose), NAADP binds to and opens Ca2+ channels on intracellular organelles, thereby increasing the intracellular Ca2+ concentration which, in turn, modulates sundry cellular processes (see Calcium signalling). Structurally, it is a dinucleotide that only differs from the house-keeping enzyme cofactor, NADP by a hydroxyl group (replacing the nicotinamide amino group) and yet this minor modification converts it into the most potent Ca2+-mobilizing second messenger yet described. NAADP acts across phyla from plants to humans.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. And a receptor being clearly present in bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes, and fatty acid metabolites with affinity for this CB receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA).

<span class="mw-page-title-main">Glutaminase</span>

Glutaminase is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor gamma</span> Nuclear receptor protein found in humans

Peroxisome proliferator- activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.

<span class="mw-page-title-main">LPAR2</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 2 also known as LPA2 is a protein that in humans is encoded by the LPAR2 gene. LPA2 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">S1PR2</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 2, also known as S1PR2 or S1P2, is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P).

<span class="mw-page-title-main">GNG2</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 is a protein that in humans is encoded by the GNG2 gene.

<span class="mw-page-title-main">PIKFYVE</span> Protein-coding gene in the species Homo sapiens

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.

<span class="mw-page-title-main">Cyclic di-AMP</span> Chemical compound

Cyclic di-AMP is a second messenger used in signal transduction in bacteria and archaea. It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum euryarchaeota.

<span class="mw-page-title-main">Antony Galione</span> British pharmacologist (born 1963)

Antony Giuseppe Galione is a British pharmacologist. He is a professor and Wellcome Trust senior investigator in the Department of Pharmacology at the University of Oxford.

References

  1. Naylor E, Arredouani A, Vasudevan SR, Lewis AM, Parkesh R, Mizote A, et al. (April 2009). "Identification of a chemical probe for NAADP by virtual screening". Nature Chemical Biology. 5 (4): 220–6. doi:10.1038/nchembio.150. PMC   2659327 . PMID   19234453.
  2. Rosen D, Lewis AM, Mizote A, Thomas JM, Aley PK, Vasudevan SR, et al. (December 2009). "Analogues of the nicotinic acid adenine dinucleotide phosphate (NAADP) antagonist Ned-19 indicate two binding sites on the NAADP receptor". The Journal of Biological Chemistry. 284 (50): 34930–4. doi: 10.1074/jbc.M109.016519 . PMC   2787355 . PMID   19826006.
  3. Park KH, Kim BJ, Shawl AI, Han MK, Lee HC, Kim UH (December 2013). "Autocrine/paracrine function of nicotinic acid adenine dinucleotide phosphate (NAADP) for glucose homeostasis in pancreatic β-cells and adipocytes". The Journal of Biological Chemistry. 288 (49): 35548–58. doi: 10.1074/jbc.M113.489278 . PMC   3853300 . PMID   24165120.
  4. Lee S, Paudel O, Jiang Y, Yang XR, Sham JS (March 2015). "CD38 mediates angiotensin II-induced intracellular Ca(2+) release in rat pulmonary arterial smooth muscle cells". American Journal of Respiratory Cell and Molecular Biology. 52 (3): 332–41. doi:10.1165/rcmb.2014-0141OC. PMC   4370261 . PMID   25078456.
  5. Davidson SM, Foote K, Kunuthur S, Gosain R, Tan N, Tyser R, et al. (December 2015). "Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore". Cardiovascular Research. 108 (3): 357–66. doi: 10.1093/cvr/cvv226 . PMC   4648198 . PMID   26395965.
  6. Pereira GJ, Antonioli M, Hirata H, Ureshino RP, Nascimento AR, Bincoletto C, et al. (February 2017). "Glutamate induces autophagy via the two-pore channels in neural cells". Oncotarget. 8 (8): 12730–12740. doi: 10.18632/oncotarget.14404 . PMC   5355049 . PMID   28055974.
  7. Hermann J, Bender M, Schumacher D, Woo MS, Shaposhnykov A, Rosenkranz SC, et al. (2020). "2+ Homeostasis in Mouse Hippocampal Neurons". Frontiers in Cell and Developmental Biology. 8: 496. doi: 10.3389/fcell.2020.00496 . PMC   7333232 . PMID   32676502.
  8. Jin X, Zhang Y, Alharbi A, Hanbashi A, Alhoshani A, Parrington J (August 2020). "Targeting Two-Pore Channels: Current Progress and Future Challenges". Trends in Pharmacological Sciences. 41 (8): 582–594. doi: 10.1016/j.tips.2020.06.002 . PMC   7365084 . PMID   32679067.