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| | ==Alpha-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Contraints in the Acyl Side Chain== | | ==Alpha-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Contraints in the Acyl Side Chain== |
| - | <StructureSection load='3oj8' size='340' side='right' caption='[[3oj8]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='3oj8' size='340' side='right'caption='[[3oj8]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3oj8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OJ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OJ8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3oj8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OJ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OJ8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=OJ8:(S)-[(2S)-6-PHENOXY-1,2,3,4-TETRAHYDRONAPHTHALEN-2-YL](5-PYRIDIN-2-YL-1,3-OXAZOL-2-YL)METHANOL'>OJ8</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wj1|2wj1]], [[2wj2|2wj2]], [[2vya|2vya]], [[3lj6|3lj6]], [[2wap|2wap]], [[3k7f|3k7f]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=OJ8:(S)-[(2S)-6-PHENOXY-1,2,3,4-TETRAHYDRONAPHTHALEN-2-YL](5-PYRIDIN-2-YL-1,3-OXAZOL-2-YL)METHANOL'>OJ8</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Faah, faah-1, Faah1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=3oj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oj8 OCA], [https://pdbe.org/3oj8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3oj8 RCSB], [https://www.ebi.ac.uk/pdbsum/3oj8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3oj8 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase Fatty acid amide hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.99 3.5.1.99] </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=3oj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oj8 OCA], [http://pdbe.org/3oj8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3oj8 RCSB], [http://www.ebi.ac.uk/pdbsum/3oj8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3oj8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Function == | |
| - | [[http://www.uniprot.org/uniprot/FAAH1_RAT FAAH1_RAT]] Degrades bioactive fatty acid amides like oleamide, the endogenous cannabinoid, anandamide and myristic amide to their corresponding acids, thereby serving to terminate the signaling functions of these molecules. Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (By similarity). | |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Fatty acid amide hydrolase]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Boger, D L]] | + | [[Category: Boger DL]] |
| - | [[Category: Mileni, M]] | + | [[Category: Mileni M]] |
| - | [[Category: Stevens, R C]] | + | [[Category: Stevens RC]] |
| - | [[Category: Enantiomer]]
| + | |
| - | [[Category: Faah]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Oxazole]]
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| - | [[Category: Protein-inhibitor complex]]
| + | |
| - | [[Category: Serine hydrolase]]
| + | |
| Structural highlights
Publication Abstract from PubMed
A series of alpha-ketooxazoles containing conformational constraints in the C2 acyl side chain of 2 (OL-135) were examined as inhibitors of fatty acid amide hydrolase (FAAH). Only one of the two possible enantiomers displayed potent FAAH inhibition (S vs R enantiomer), and their potency is comparable or improved relative to 2, indicating that the conformational restriction in the C2 acyl side chain is achievable. A cocrystal X-ray structure of the alpha-ketoheterocycle 12 bound to a humanized variant of rat FAAH revealed its binding details, confirmed that the (S)-enantiomer is the bound active inhibitor, shed light on the origin of the enantiomeric selectivity, and confirmed that the catalytic Ser241 is covalently bound to the electrophilic carbonyl as a deprotonated hemiketal. Preliminary in vivo characterization of the inhibitors 12 and 14 is reported demonstrating that they raise brain anandamide levels following either intraperitoneal (ip) or oral (po) administration indicative of effective in vivo FAAH inhibition. Significantly, the oral administration of 12 caused dramatic accumulation of anandamide in the brain, with peak levels achieved between 1.5 and 3 h, and these elevations were maintained over 9 h. Additional studies of these two representative members of the series (12 and 14) in models of thermal hyperalgesia and neuropathic pain are reported, including the demonstration that 12 administered orally significantly attenuated mechanical (>6 h) and cold (>9 h) allodynia for sustained periods consistent with its long-acting effects in raising the endogenous concentration of anandamide.
Reversible competitive alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics.,Ezzili C, Mileni M, McGlinchey N, Long JZ, Kinsey SG, Hochstatter DG, Stevens RC, Lichtman AH, Cravatt BF, Bilsky EJ, Boger DL J Med Chem. 2011 Apr 28;54(8):2805-22. Epub 2011 Mar 23. PMID:21428410[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ezzili C, Mileni M, McGlinchey N, Long JZ, Kinsey SG, Hochstatter DG, Stevens RC, Lichtman AH, Cravatt BF, Bilsky EJ, Boger DL. Reversible competitive alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase containing additional conformational constraints in the acyl side chain: orally active, long-acting analgesics. J Med Chem. 2011 Apr 28;54(8):2805-22. Epub 2011 Mar 23. PMID:21428410 doi:10.1021/jm101597x
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