3uuo

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==The discovery of potent, selectivity, and orally bioavailable pyrozoloquinolines as PDE10 inhibitors for the treatment of Schizophrenia==
==The discovery of potent, selectivity, and orally bioavailable pyrozoloquinolines as PDE10 inhibitors for the treatment of Schizophrenia==
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<StructureSection load='3uuo' size='340' side='right' caption='[[3uuo]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
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<StructureSection load='3uuo' size='340' side='right'caption='[[3uuo]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3uuo]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UUO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UUO FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3uuo]] 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=3UUO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UUO FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0CV:6-METHOXY-3,8-DIMETHYL-4-(PIPERAZIN-1-YL)-1H-PYRAZOLO[3,4-B]QUINOLINE'>0CV</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.11&#8491;</td></tr>
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<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 Homo sapiens])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0CV:6-METHOXY-3,8-DIMETHYL-4-(PIPERAZIN-1-YL)-1H-PYRAZOLO[3,4-B]QUINOLINE'>0CV</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<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=3uuo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uuo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3uuo RCSB], [http://www.ebi.ac.uk/pdbsum/3uuo PDBsum]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3uuo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uuo OCA], [https://pdbe.org/3uuo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3uuo RCSB], [https://www.ebi.ac.uk/pdbsum/3uuo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3uuo ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a approximately 6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.
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The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia.,Ho GD, Yang SW, Smotryski J, Bercovici A, Nechuta T, Smith EM, McElroy W, Tan Z, Tulshian D, McKittrick B, Greenlee WJ, Hruza A, Xiao L, Rindgen D, Mullins D, Guzzi M, Zhang X, Bleickardt C, Hodgson R Bioorg Med Chem Lett. 2012 Jan 15;22(2):1019-22. Epub 2011 Dec 9. PMID:22222034<ref>PMID:22222034</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Phosphodiesterase|Phosphodiesterase]]
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Bercovici, A]]
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[[Category: Large Structures]]
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[[Category: Bleickardt, C]]
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[[Category: Bercovici A]]
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[[Category: Greenlee, W J]]
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[[Category: Bleickardt C]]
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[[Category: Guzzi, M]]
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[[Category: Greenlee WJ]]
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[[Category: Ho, G D]]
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[[Category: Guzzi M]]
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[[Category: Hodgson, R]]
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[[Category: Ho GD]]
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[[Category: Hruza, A]]
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[[Category: Hodgson R]]
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[[Category: McElroy, W]]
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[[Category: Hruza A]]
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[[Category: Mckittrick, B]]
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[[Category: McElroy W]]
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[[Category: Mullins, D]]
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[[Category: Mckittrick B]]
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[[Category: Nechuta, T]]
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[[Category: Mullins D]]
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[[Category: Rindgen, D]]
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[[Category: Nechuta T]]
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[[Category: Smith, E M]]
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[[Category: Rindgen D]]
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[[Category: Smotryski, J]]
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[[Category: Smith EM]]
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[[Category: Tan, Z]]
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[[Category: Smotryski J]]
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[[Category: Tulshian, D]]
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[[Category: Tan Z]]
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[[Category: Xiao, L]]
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[[Category: Tulshian D]]
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[[Category: Yang, S]]
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[[Category: Xiao L]]
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[[Category: Zhang, X]]
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[[Category: Yang S]]
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[[Category: Hydrolase]]
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[[Category: Zhang X]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Inhibitor complex]]
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[[Category: Mg binding]]
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[[Category: Zn binding]]
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Current revision

The discovery of potent, selectivity, and orally bioavailable pyrozoloquinolines as PDE10 inhibitors for the treatment of Schizophrenia

PDB ID 3uuo

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