|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Potent and Selective Phosphodiesterase 10A Inhibitors== | | ==Potent and Selective Phosphodiesterase 10A Inhibitors== |
| - | <StructureSection load='4fcd' size='340' side='right' caption='[[4fcd]], [[Resolution|resolution]] 2.02Å' scene=''> | + | <StructureSection load='4fcd' size='340' side='right'caption='[[4fcd]], [[Resolution|resolution]] 2.02Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4fcd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FCD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FCD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4fcd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FCD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FCD FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0T6:1-(2-CHLOROPHENYL)-6,8-DIMETHOXY-3-METHYLIMIDAZO[5,1-C][1,2,4]BENZOTRIAZINE'>0T6</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0T6:1-(2-CHLOROPHENYL)-6,8-DIMETHOXY-3-METHYLIMIDAZO[5,1-C][1,2,4]BENZOTRIAZINE'>0T6</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fcb|4fcb]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4fcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fcd OCA], [https://pdbe.org/4fcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fcd RCSB], [https://www.ebi.ac.uk/pdbsum/4fcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fcd ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE10A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4fcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fcd OCA], [http://pdbe.org/4fcd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fcd RCSB], [http://www.ebi.ac.uk/pdbsum/4fcd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fcd ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref> | + | [https://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 20: |
Line 18: |
| | </div> | | </div> |
| | <div class="pdbe-citations 4fcd" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4fcd" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Parris, K D]] | + | [[Category: Large Structures]] |
| - | [[Category: Binding site]] | + | [[Category: Parris KD]] |
| - | [[Category: Cyclic amp]]
| + | |
| - | [[Category: Cyclic gmp]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Hydrolysis]]
| + | |
| - | [[Category: Ligand]]
| + | |
| - | [[Category: Phosphodiesterase inhibitor]]
| + | |
| - | [[Category: Phosphoric diester hydrolase]]
| + | |
| - | [[Category: Recombinant protein]]
| + | |
| - | [[Category: Structure-activity relationship]]
| + | |
| Structural highlights
Function
PDE10_HUMAN Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1]
Publication Abstract from PubMed
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4nM), demonstrated high selectivity (>200x) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2mg/kg).
Novel triazines as potent and selective phosphodiesterase 10A inhibitors.,Malamas MS, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, Egerland U, Hage T, Ni Y, Erdei J, Fan KY, Parris K, Marquis KL, Grauer S, Brennan J, Navarra R, Graf R, Harrison BL, Robichaud A, Kronbach T, Pangalos MN, Brandon NJ, Hoefgen N Bioorg Med Chem Lett. 2012 Sep 15;22(18):5876-84. Epub 2012 Jul 31. PMID:22902656[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385
- ↑ Malamas MS, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, Egerland U, Hage T, Ni Y, Erdei J, Fan KY, Parris K, Marquis KL, Grauer S, Brennan J, Navarra R, Graf R, Harrison BL, Robichaud A, Kronbach T, Pangalos MN, Brandon NJ, Hoefgen N. Novel triazines as potent and selective phosphodiesterase 10A inhibitors. Bioorg Med Chem Lett. 2012 Sep 15;22(18):5876-84. Epub 2012 Jul 31. PMID:22902656 doi:http://dx.doi.org/10.1016/j.bmcl.2012.07.076
|
