4bbx

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{{STRUCTURE_4bbx| PDB=4bbx | SCENE= }}
 
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===Discovery of a potent, selective and orally active PDE10A inhibitor for the treatment of schizophrenia===
 
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==Function==
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==Discovery of a potent, selective and orally active PDE10A inhibitor for the treatment of schizophrenia==
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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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<StructureSection load='4bbx' size='340' side='right'caption='[[4bbx]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4bbx]] 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=4BBX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BBX FirstGlance]. <br>
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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]] 2.5&#8491;</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=LKF:4-[3-[1-[(2S)-2-METHOXYPROPYL]PYRAZOL-4-YL]-2-METHYL-IMIDAZO[1,2-A]PYRAZIN-8-YL]MORPHOLINE'>LKF</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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'>[https://proteopedia.org/fgij/fg.htm?mol=4bbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbx OCA], [https://pdbe.org/4bbx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bbx RCSB], [https://www.ebi.ac.uk/pdbsum/4bbx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bbx ProSAT]</span></td></tr>
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</table>
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== Function ==
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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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We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high throughput screening (HTS) campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a methoxyethylpyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity- and structure-properties-relationships (SAR and SPR) resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and good pharmacokinetic profile in rats.
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==About this Structure==
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Discovery of a potent, selective and orally active PDE10A inhibitor for the potential treatment of schizophrenia.,Bartolome-Nebreda JM, Delgado F, Martin ML, Martinez-Viturro CM, Pastor J, Tong HM, Iturrino L, Macdonald GJ, Sanderson WE, Megens A, Langlois X, Somers M, Vanhoof G, Conde Ceide S J Med Chem. 2014 Apr 23. PMID:24758746<ref>PMID:24758746</ref>
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[[4bbx]] 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=4BBX OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<references group="xtra"/><references/>
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</div>
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<div class="pdbe-citations 4bbx" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Bartolome-Nebreda, J M.]]
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[[Category: Large Structures]]
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[[Category: Conde-Ceide, S.]]
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[[Category: Bartolome-Nebreda JM]]
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[[Category: Delgado, F.]]
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[[Category: Conde-Ceide S]]
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[[Category: Iturrino, L.]]
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[[Category: Delgado F]]
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[[Category: Langlois, X.]]
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[[Category: Iturrino L]]
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[[Category: Macdonald, G J.]]
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[[Category: Langlois X]]
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[[Category: Martin, M L.]]
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[[Category: Macdonald GJ]]
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[[Category: Martinez-Viturro, C M.]]
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[[Category: Martin ML]]
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[[Category: Megens, A.]]
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[[Category: Martinez-Viturro CM]]
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[[Category: Pastor, J.]]
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[[Category: Megens A]]
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[[Category: Sanderson, W.]]
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[[Category: Pastor J]]
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[[Category: Somers, M.]]
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[[Category: Sanderson W]]
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[[Category: Tong, H M.]]
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[[Category: Somers M]]
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[[Category: Vanhoof, G.]]
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[[Category: Tong HM]]
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[[Category: Hydrolase]]
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[[Category: Vanhoof G]]
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[[Category: Inhibitor complex]]
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[[Category: Magnesium binding]]
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[[Category: Phosphodiesterase inhibitor]]
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[[Category: Zinc binding]]
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Current revision

Discovery of a potent, selective and orally active PDE10A inhibitor for the treatment of schizophrenia

PDB ID 4bbx

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