CCG-4986

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CCG-4986
Structure of CCG-4986.png
Identifiers
  • methyl-N-[(4-chlorophenyl)sulfonyl]-4-nitrobenzenesulfinimidoate
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.161.330 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H11ClN2O5S2
Molar mass 374.81 g·mol−1
3D model (JSmol)
  • O=[N](=O)c1ccc(cc1)\S(\OC)=N\S(=O)(=O)c(cc2)ccc2Cl
  • InChI=1S/C13H11ClN2O5S2/c1-21-22(12-6-4-11(5-7-12)16(17)18)15-23(19,20)13-8-2-10(14)3-9-13/h2-9H,1H3
  • Key:GIFNUYPIOIDEGE-UHFFFAOYSA-N
   (verify)

CCG-4986 is a drug which is the first non-peptide compound discovered that acts as a selective inhibitor of the regulator of G protein signalling protein subtype RGS4. [1] [2] Regulators of G protein signalling are proteins which act to limit and shorten the response produced inside a cell following activation of a G protein-coupled receptor. Since different RGS subtypes are expressed in different tissues and are associated with particular receptors, this makes it possible for selective inhibitors of RGS proteins to be developed, which should be able to enhance the activity of a particular receptor in a defined target tissue, but not elsewhere in the body. [3] [4] [5] [6] [7] [8] [9] [10]

Related Research Articles

<span class="mw-page-title-main">Opioid receptor</span> Group of biological receptors

Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.

Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.

Sigma receptors (σ-receptors) are protein receptors that bind ligands such as 4-PPBP, SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.

μ-opioid receptor Protein-coding gene in the species Homo sapiens, named for its ligand morphine

The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.

δ-opioid receptor Opioid receptor

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

<span class="mw-page-title-main">RGS4</span> Protein-coding gene in the species Homo sapiens

Regulator of G protein signaling 4 also known as RGP4 is a protein that in humans is encoded by the RGS4 gene. RGP4 regulates G protein signaling.

<span class="mw-page-title-main">RGS2</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 2 is a protein that in humans is encoded by the RGS2 gene. It is part of a larger family of RGS proteins that control signalling through G-protein coupled receptors (GPCR).

<span class="mw-page-title-main">GNAI1</span> Protein-coding gene in humans

Guanine nucleotide-binding protein G(i), alpha-1 subunit is a protein that in humans is encoded by the GNAI1 gene.

<span class="mw-page-title-main">GNAO1</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(o) subunit alpha is a protein that in humans is encoded by the GNAO1 gene.

<span class="mw-page-title-main">RGS16</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 16 is a protein that in humans is encoded by the RGS16 gene.

<span class="mw-page-title-main">RGS19</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 19 is a protein that in humans is encoded by the RGS19 gene.

<span class="mw-page-title-main">RGS3</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 3 is a protein that in humans is encoded by the RGS3 gene.

<span class="mw-page-title-main">RGS5</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 5 is a protein that in humans is encoded by the RGS5 gene.

<span class="mw-page-title-main">RGS20</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 20 is a protein that in humans is encoded by the RGS20 gene.

<span class="mw-page-title-main">RGS10</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 10 is a protein that in humans is encoded by the RGS10 gene.

<span class="mw-page-title-main">RGS12</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 12 is a protein that in humans is encoded by the RGS12 gene.

<span class="mw-page-title-main">RGS8</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 8 is a protein that in humans is encoded by the RGS8 gene.

<span class="mw-page-title-main">RGS9</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signalling 9, also known as RGS9, is a human gene, which codes for a protein involved in regulation of signal transduction inside cells. Members of the RGS family, such as RGS9, are signaling proteins that suppress the activity of G proteins by promoting their deactivation.[supplied by OMIM]

<span class="mw-page-title-main">GNAI3</span> Protein-coding gene in humans

Guanine nucleotide-binding protein G(k) subunit alpha is a protein that in humans is encoded by the GNAI3 gene.

<span class="mw-page-title-main">RGS17</span> Protein-coding gene in the species Homo sapiens

Regulator of G-protein signaling 17 is a protein that in humans is encoded by the RGS17 gene.

References

  1. ↑ Roman DL, Talbot JN, Roof RA, Sunahara RK, Traynor JR, Neubig RR (January 2007). "Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay". Molecular Pharmacology. 71 (1): 169–75. doi:10.1124/mol.106.028670. PMID   17012620. S2CID   22699604.
  2. ↑ Kimple AJ, Willard FS, Giguère PM, Johnston CA, Mocanu V, Siderovski DP (September 2007). "The RGS protein inhibitor CCG-4986 is a covalent modifier of the RGS4 Gα-interaction face". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1774 (9): 1213–20. doi:10.1016/j.bbapap.2007.06.002. PMC   2084260 . PMID   17660054.
  3. ↑ Garzón J, Rodríguez-Muñoz M, de la Torre-Madrid E, Sánchez-Blázquez P (June 2005). "Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS". Psychopharmacology. 180 (1): 1–11. doi:10.1007/s00213-005-2248-9. hdl: 10261/154655 . PMID   15830230. S2CID   21952312.
  4. ↑ Georgoussi Z, Leontiadis L, Mazarakou G, Merkouris M, Hyde K, Hamm H (June 2006). "Selective interactions between G protein subunits and RGS4 with the C-terminal domains of the mu- and delta-opioid receptors regulate opioid receptor signaling". Cellular Signalling. 18 (6): 771–82. doi:10.1016/j.cellsig.2005.07.003. PMID   16120478.
  5. ↑ Hu W, Li F, Mahavadi S, Murthy KS (May 2008). "Interleukin-1beta up-regulates RGS4 through the canonical IKK2/IkappaBalpha/NF-kappaB pathway in rabbit colonic smooth muscle". The Biochemical Journal. 412 (1): 35–43. doi:10.1042/BJ20080042. PMC   3707494 . PMID   18260825.
  6. ↑ Paspalas CD, Selemon LD, Arnsten AF (January 2009). "Mapping the Regulator of G Protein Signaling 4 (RGS4): Presynaptic and Postsynaptic Substrates for Neuroregulation in Prefrontal Cortex". Cerebral Cortex. 19 (9): 2145–55. doi:10.1093/cercor/bhn235. PMC   2722426 . PMID   19153107.
  7. ↑ Prasad KM, Almasy L, Gur RC, Gur RE, Pogue-Geile M, Chowdari KV, Talkowski ME, Nimgaonkar VL (March 2009). "RGS4 Polymorphisms Associated With Variability of Cognitive Performance in a Family-Based Schizophrenia Sample". Schizophrenia Bulletin. 36 (5): 983–90. doi:10.1093/schbul/sbp002. PMC   2930339 . PMID   19282471.
  8. ↑ Hu W, Li F, Mahavadi S, Murthy KS (June 2009). "Upregulation of RGS4 expression by IL-1β in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3β pathway". American Journal of Physiology. Cell Physiology. 296 (6): C1310–20. doi:10.1152/ajpcell.00573.2008. PMC   2692422 . PMID   19369446.
  9. ↑ Leontiadis LJ, Papakonstantinou MP, Georgoussi Z (July 2009). "Regulator of G protein signaling 4 confers selectivity to specific G proteins to modulate mu- and delta-opioid receptor signaling". Cellular Signalling. 21 (7): 1218–28. doi:10.1016/j.cellsig.2009.03.013. PMID   19324084.
  10. ↑ Song KS, Kim HJ, Kim K, Lee JG, Yoon JH (July 2009). "Regulator of G-protein signaling 4 suppresses LPS-induced MUC5AC overproduction in the airway". American Journal of Respiratory Cell and Molecular Biology. 41 (1): 40–9. doi:10.1165/rcmb.2008-0280OC. PMID   19059885.


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