4tpm

From Proteopedia

(Difference between revisions)

Revision as of 21:42, 15 October 2015

Crystal structure of 2-(3-alkoxy-1-azetidinyl) quinolines as PDE10A Inhibitors

Structural highlights

4tpm is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	4tpp
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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

We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.

Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility.,Rzasa RM, Frohn MJ, Andrews KL, Chmait S, Chen N, Clarine JG, Davis C, Eastwood HA, Horne DB, Hu E, Jones AD, Kaller MR, Kunz RK, Miller S, Monenschein H, Nguyen T, Pickrell AJ, Porter A, Reichelt A, Zhao X, Treanor JJ, Allen JR Bioorg Med Chem. 2014 Oct 22;22(23):6570-6585. doi: 10.1016/j.bmc.2014.10.013. PMID:25456383^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Rzasa RM, Frohn MJ, Andrews KL, Chmait S, Chen N, Clarine JG, Davis C, Eastwood HA, Horne DB, Hu E, Jones AD, Kaller MR, Kunz RK, Miller S, Monenschein H, Nguyen T, Pickrell AJ, Porter A, Reichelt A, Zhao X, Treanor JJ, Allen JR. Synthesis and preliminary biological evaluation of potent and selective 2-(3-alkoxy-1-azetidinyl) quinolines as novel PDE10A inhibitors with improved solubility. Bioorg Med Chem. 2014 Oct 22;22(23):6570-6585. doi: 10.1016/j.bmc.2014.10.013. PMID:25456383 doi:http://dx.doi.org/10.1016/j.bmc.2014.10.013

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4tpm"

Categories: Chmait, S | Hydrolase-hydrolase inhibitor complex | Pde10a | Quinoline

@@ Line 5: / Line 5: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=35E:[1-(3-{[1-(QUINOLIN-2-YL)AZETIDIN-3-YL]OXY}PYRAZIN-2-YL)PIPERIDIN-4-YL]METHANOL'>35E</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">[[4tpp|4tpp]]</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=4tpm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tpm RCSB], [http://www.ebi.ac.uk/pdbsum/4tpm PDBsum]</span></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=4tpm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpm OCA], [http://pdbe.org/4tpm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tpm RCSB], [http://www.ebi.ac.uk/pdbsum/4tpm PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4tpm" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4tpm

From Proteopedia

Revision as of 21:42, 15 October 2015

Crystal structure of 2-(3-alkoxy-1-azetidinyl) quinolines as PDE10A Inhibitors

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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