Fatty acid amide hydrolase: Difference between revisions

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* [[Anandamide]] (''N''-arachidonoylethanolamine), an [[endocannabinoid]]<ref name="pmid11470906">{{cite journal | vauthors = Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH | title = Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 16 | pages = 9371–6 | date = July 2001 | pmid = 11470906 | pmc = 55427 | doi = 10.1073/pnas.161191698 }}</ref>
* [[Anandamide]] (''N''-arachidonoylethanolamine), an [[endocannabinoid]]<ref name="pmid11470906">{{cite journal | vauthors = Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH | title = Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 16 | pages = 9371–6 | date = July 2001 | pmid = 11470906 | pmc = 55427 | doi = 10.1073/pnas.161191698 }}</ref>
* Other ''N''-acylethanolamines, such as [[Oleoylethanolamide|''N''-oleoylethanolamine]] and [[Palmitoylethanolamide|''N''-palmitoylethanolamine]]<ref name="pmid15533037">{{cite journal | vauthors = Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, Cravatt BF | title = Assignment of endogenous substrates to enzymes by global metabolite profiling | journal = Biochemistry | volume = 43 | issue = 45 | pages = 14332–9 | date = November 2004 | pmid = 15533037 | doi = 10.1021/bi0480335 }}</ref>
*[[2-Arachidonoylglycerol|2-arachidonoylglycerol]] (2-AG), an endocannabinoid.<ref>{{Cite journal|date=2000-11-01|title=The fatty acid amide hydrolase (FAAH)|url=https://www.sciencedirect.com/science/article/pii/S0009308400001900|journal=Chemistry and Physics of Lipids|language=en|volume=108|issue=1-2|pages=107–121|doi=10.1016/S0009-3084(00)00190-0|issn=0009-3084}}</ref>
* Other [[N-acylethanolamine|''N''-acylethanolamines]], such as [[Oleoylethanolamide|''N''-oleoylethanolamine]] and [[Palmitoylethanolamide|''N''-palmitoylethanolamine]]<ref name="pmid15533037">{{cite journal | vauthors = Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, Cravatt BF | title = Assignment of endogenous substrates to enzymes by global metabolite profiling | journal = Biochemistry | volume = 43 | issue = 45 | pages = 14332–9 | date = November 2004 | pmid = 15533037 | doi = 10.1021/bi0480335 }}</ref>
* The sleep-inducing lipid [[oleamide]]<ref name="pmid7770779">{{cite journal | vauthors = Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA | title = Chemical characterization of a family of brain lipids that induce sleep | journal = Science | volume = 268 | issue = 5216 | pages = 1506–9 | date = June 1995 | pmid = 7770779 | doi = 10.1126/science.7770779 }}</ref>
* The sleep-inducing lipid [[oleamide]]<ref name="pmid7770779">{{cite journal | vauthors = Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA | title = Chemical characterization of a family of brain lipids that induce sleep | journal = Science | volume = 268 | issue = 5216 | pages = 1506–9 | date = June 1995 | pmid = 7770779 | doi = 10.1126/science.7770779 }}</ref>
* The ''N''-acyltaurines, which are agonists of the [[transient receptor potential]] (TRP) family of calcium channels.<ref name="pmid16866345">{{cite journal | vauthors = Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF | title = A FAAH-regulated class of N-acyl taurines that activates TRP ion channels | journal = Biochemistry | volume = 45 | issue = 30 | pages = 9007–15 | date = August 2006 | pmid = 16866345 | doi = 10.1021/bi0608008 }}</ref>
* The ''N''-acyltaurines, which are agonists of the [[transient receptor potential]] (TRP) family of calcium channels.<ref name="pmid16866345">{{cite journal | vauthors = Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF | title = A FAAH-regulated class of N-acyl taurines that activates TRP ion channels | journal = Biochemistry | volume = 45 | issue = 30 | pages = 9007–15 | date = August 2006 | pmid = 16866345 | doi = 10.1021/bi0608008 }}</ref>
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Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat [[anxiety disorders]].<ref name=Panlilio2013rev/><ref name="pmid24325918">{{cite journal | vauthors = Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A | title = Amygdala FAAH and anandamide: mediating protection and recovery from stress | journal = Trends in Pharmacological Sciences | volume = 34 | issue = 11 | pages = 637–44 | date = November 2013 | pmid = 24325918 | pmc = 4169112 | doi = 10.1016/j.tips.2013.08.008 }}</ref><ref name="pmid27456243">{{cite journal | vauthors = Berardi A, Schelling G, Campolongo P | title = The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings | journal = Pharmacological Research | volume = 111 | issue =  | pages = 668–78 | date = September 2016 | pmid = 27456243 | doi = 10.1016/j.phrs.2016.07.024 }}</ref>
Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat [[anxiety disorders]].<ref name=Panlilio2013rev/><ref name="pmid24325918">{{cite journal | vauthors = Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A | title = Amygdala FAAH and anandamide: mediating protection and recovery from stress | journal = Trends in Pharmacological Sciences | volume = 34 | issue = 11 | pages = 637–44 | date = November 2013 | pmid = 24325918 | pmc = 4169112 | doi = 10.1016/j.tips.2013.08.008 }}</ref><ref name="pmid27456243">{{cite journal | vauthors = Berardi A, Schelling G, Campolongo P | title = The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings | journal = Pharmacological Research | volume = 111 | issue =  | pages = 668–78 | date = September 2016 | pmid = 27456243 | doi = 10.1016/j.phrs.2016.07.024 }}</ref>


==Inhibitors and inactivators==
== Inhibitors and inactivators ==
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Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of [[Enzyme inhibitor#Irreversible inhibitors|irreversible]] and [[Enzyme inhibitor#Reversible inhibitors|reversible]] inhibitors of this enzyme have been developed.<ref name="pmid19367506">{{cite journal | vauthors = Janero DR, Vadivel SK, Makriyannis A | title = Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies | journal = International Review of Psychiatry (Abingdon, England) | volume = 21 | issue = 2 | pages = 122–33 | date = April 2009 | pmid = 19367506 | pmc = 5531754 | doi = 10.1080/09540260902782778 }}</ref><ref name="pmid20544003">{{cite journal | vauthors = Ahn K, Johnson DS, Cravatt BF | title = Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders | journal = Expert Opinion on Drug Discovery | volume = 4 | issue = 7 | pages = 763–784 | date = July 2009 | pmid = 20544003 | pmc = 2882713 | doi = 10.1517/17460440903018857 }}</ref><ref name="pmid20047159">{{cite journal | vauthors = Petrosino S, Di Marzo V | title = FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels | journal = Current Opinion in Investigational Drugs | volume = 11 | issue = 1 | pages = 51–62 | date = January 2010 | pmid = 20047159 | doi =  }}</ref><ref name="pmid20370710">{{cite journal | vauthors = Minkkilä A, Saario S, Nevalainen T | title = Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors | journal = Current Topics in Medicinal Chemistry | volume = 10 | issue = 8 | pages = 828–58 | year = 2010 | pmid = 20370710 | doi =  10.2174/156802610791164238}}</ref><ref name="pmid21631410">{{cite journal | vauthors = Khanna IK, Alexander CW | title = Fatty acid amide hydrolase inhibitors--progress and potential | journal = CNS & Neurological Disorders Drug Targets | volume = 10 | issue = 5 | pages = 545–58 | date = August 2011 | pmid = 21631410 | doi = 10.2174/187152711796234989 }}</ref><ref name="pmid23488865">{{cite journal | vauthors = Bisogno T, Maccarrone M | title = Latest advances in the discovery of fatty acid amide hydrolase inhibitors | journal = Expert Opinion on Drug Discovery | volume = 8 | issue = 5 | pages = 509–22 | date = May 2013 | pmid = 23488865 | doi = 10.1517/17460441.2013.780021 }}</ref><ref name="pmid24135210">{{cite journal | vauthors = Pertwee RG | title = Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications | journal = The Proceedings of the Nutrition Society | volume = 73 | issue = 1 | pages = 96–105 | date = February 2014 | pmid = 24135210 | doi = 10.1017/S0029665113003649 }}</ref><ref name="pmid26413912">{{cite journal | vauthors = Lodola A, Castelli R, Mor M, Rivara S | title = Fatty acid amide hydrolase inhibitors: a patent review (2009-2014) | journal = Expert Opinion on Therapeutic Patents | volume = 25 | issue = 11 | pages = 1247–66 | year = 2015 | pmid = 26413912 | doi = 10.1517/13543776.2015.1067683 }}</ref>
Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of [[Enzyme inhibitor#Irreversible inhibitors|irreversible]] and [[Enzyme inhibitor#Reversible inhibitors|reversible]] inhibitors of this enzyme have been developed.<ref name="pmid19367506">{{cite journal | vauthors = Janero DR, Vadivel SK, Makriyannis A |authorlink3=Alexandros Makriyannis| title = Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies | journal = International Review of Psychiatry (Abingdon, England) | volume = 21 | issue = 2 | pages = 122–33 | date = April 2009 | pmid = 19367506 | pmc = 5531754 | doi = 10.1080/09540260902782778 }}</ref><ref name="pmid20544003">{{cite journal | vauthors = Ahn K, Johnson DS, Cravatt BF | title = Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders | journal = Expert Opinion on Drug Discovery | volume = 4 | issue = 7 | pages = 763–784 | date = July 2009 | pmid = 20544003 | pmc = 2882713 | doi = 10.1517/17460440903018857 }}</ref><ref name="pmid20047159">{{cite journal | vauthors = Petrosino S, Di Marzo V | title = FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels | journal = Current Opinion in Investigational Drugs | volume = 11 | issue = 1 | pages = 51–62 | date = January 2010 | pmid = 20047159 | doi =  }}</ref><ref name="pmid20370710">{{cite journal | vauthors = Minkkilä A, Saario S, Nevalainen T | title = Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors | journal = Current Topics in Medicinal Chemistry | volume = 10 | issue = 8 | pages = 828–58 | year = 2010 | pmid = 20370710 | doi =  10.2174/156802610791164238}}</ref><ref name="pmid21631410">{{cite journal | vauthors = Khanna IK, Alexander CW | title = Fatty acid amide hydrolase inhibitors--progress and potential | journal = CNS & Neurological Disorders Drug Targets | volume = 10 | issue = 5 | pages = 545–58 | date = August 2011 | pmid = 21631410 | doi = 10.2174/187152711796234989 }}</ref><ref name="pmid23488865">{{cite journal | vauthors = Bisogno T, Maccarrone M | title = Latest advances in the discovery of fatty acid amide hydrolase inhibitors | journal = Expert Opinion on Drug Discovery | volume = 8 | issue = 5 | pages = 509–22 | date = May 2013 | pmid = 23488865 | doi = 10.1517/17460441.2013.780021 }}</ref><ref name="pmid24135210">{{cite journal | vauthors = Pertwee RG | title = Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications | journal = The Proceedings of the Nutrition Society | volume = 73 | issue = 1 | pages = 96–105 | date = February 2014 | pmid = 24135210 | doi = 10.1017/S0029665113003649 }}</ref><ref name="pmid26413912">{{cite journal | vauthors = Lodola A, Castelli R, Mor M, Rivara S | title = Fatty acid amide hydrolase inhibitors: a patent review (2009-2014) | journal = Expert Opinion on Therapeutic Patents | volume = 25 | issue = 11 | pages = 1247–66 | year = 2015 | pmid = 26413912 | doi = 10.1517/13543776.2015.1067683 }}</ref>


Some of the more significant compounds are listed below;
Some of the more significant compounds are listed below;
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* [[AM374]], palmitylsulfonyl fluoride, one of the first FAAH inhibitors developed for ''in vitro'' use, but too reactive for research ''in vivo''  
* [[AM374]], palmitylsulfonyl fluoride, one of the first FAAH inhibitors developed for ''in vitro'' use, but too reactive for research ''in vivo''  
* [[ARN2508]], derivative of [[flurbiprofen]], dual FAAH / COX inhibitor
* [[ARN2508]], derivative of [[flurbiprofen]], dual FAAH / COX inhibitor
* [[BIA 10-2474]] ([[Bial |Bial-Portela]] & Ca. SA, [[Portugal]]) has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.<ref>{{Cite journal  | pmid = | pmc = | year = 2016 | author1 = Enserink | first1 = Martin | name-list-format = vanc | title = More Details Emerge on Fateful French Drug Trial | journal = [[Science (magazine)|Science]] | format = online | volume = | issue = January 16 | pages = | url = http://www.sciencemag.org/news/2016/01/more-details-emerge-fateful-french-drug-trial | access-date = 16 January 2016 | doi = }}</ref>  Many other pharmaceutical companies have previously taken other FAAH inhibitors into clinical trials without reporting such adverse events.
* [[BIA 10-2474]] ([[Bial |Bial-Portela]] & Ca. SA, [[Portugal]]) has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.<ref>{{Cite journal  | pmid = | pmc = | year = 2016 | author1 = Enserink | first1 = Martin | name-list-format = vanc | title = More Details Emerge on Fateful French Drug Trial | journal = [[Science (magazine)|Science]] | format = online | volume = | issue = January 16 | pages = | url = http://www.sciencemag.org/news/2016/01/more-details-emerge-fateful-french-drug-trial | access-date = 16 January 2016 | doi = 10.1126/science.aae0247 }}</ref>  Many other pharmaceutical companies have previously taken other FAAH inhibitors into clinical trials without reporting such adverse events.
* [[BMS-469908]]<ref name="pmid23512546">{{cite journal | vauthors = Blankman JL, Cravatt BF | title = Chemical probes of endocannabinoid metabolism | journal = Pharmacological Reviews | volume = 65 | issue = 2 | pages = 849–71 | date = April 2013 | pmid = 23512546 | pmc = 3639726 | doi = 10.1124/pr.112.006387 }}</ref>
* [[BMS-469908]]<ref name="pmid23512546">{{cite journal | vauthors = Blankman JL, Cravatt BF | title = Chemical probes of endocannabinoid metabolism | journal = Pharmacological Reviews | volume = 65 | issue = 2 | pages = 849–71 | date = April 2013 | pmid = 23512546 | pmc = 3639726 | doi = 10.1124/pr.112.006387 }}</ref>
* [[CAY-10402]]
* [[CAY-10402]]
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* [[URB694]]
* [[URB694]]
* [[URB937]]
* [[URB937]]
* [[VER-156084]]<ref name="pmid19515560">{{cite journal | vauthors = Hart T, Macias AT, Benwell K, Brooks T, D'Alessandro J, Dokurno P, Francis G, Gibbons B, Haymes T, Kennett G, Lightowler S, Mansell H, Matassova N, Misra A, Padfield A, Parsons R, Pratt R, Robertson A, Walls S, Wong M, Roughley S  | display-authors = 6 | title = Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas | journal = Bioorganic & Medicinal Chemistry Letters | volume = 19 | issue = 15 | pages = 4241–4 | date = August 2009 | pmid = 19515560 | doi = 10.1016/j.bmcl.2009.05.097 }}</ref>
* [[VER-156084]] ([[Vernalis plc|Vernalis]])<ref name="pmid19515560">{{cite journal | vauthors = Hart T, Macias AT, Benwell K, Brooks T, D'Alessandro J, Dokurno P, Francis G, Gibbons B, Haymes T, Kennett G, Lightowler S, Mansell H, Matassova N, Misra A, Padfield A, Parsons R, Pratt R, Robertson A, Walls S, Wong M, Roughley S  | display-authors = 6 | title = Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas | journal = Bioorganic & Medicinal Chemistry Letters | volume = 19 | issue = 15 | pages = 4241–4 | date = August 2009 | pmid = 19515560 | doi = 10.1016/j.bmcl.2009.05.097 }}</ref>
* [[V-158866]] in clinical trials for neuropathic pain following spinal injury,<ref>{{ClinicalTrialsGov| NCT01748695| A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury}}</ref> and spasticity associated with multiple sclerosis. Structure not revealed though Vernalis holds several patents in the area.<ref>{{cite patent | country = US | number = 8450346 | status = granted | title =  Azetidine derivatives as FAAH inhibitors | pubdate = 28 May 2013 | fdate = 27 Feb 2009 | pridate = 4 March 2008 | invent = Roughly S, Walls S, Hart T, Parsons R, Brough P, Graham C, Macias A | assign1 = Vernalis (R&D) Ltd. }}</ref><ref name="pmid22209458">{{cite journal | vauthors = Roughley SD, Browne H, Macias AT, Benwell K, Brooks T, D'Alessandro J, Daniels Z, Dugdale S, Francis G, Gibbons B, Hart T, Haymes T, Kennett G, Lightowler S, Matassova N, Mansell H, Merrett A, Misra A, Padfield A, Parsons R, Pratt R, Robertson A, Simmonite H, Tan K, Walls SB, Wong M | display-authors = 6 | title = Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity | journal = Bioorganic & Medicinal Chemistry Letters | volume = 22 | issue = 2 | pages = 901–6 | date = January 2012 | pmid = 22209458 | doi = 10.1016/j.bmcl.2011.12.032 }}</ref>
* [[V-158866]] ([[Vernalis plc|Vernalis]]) in clinical trials for neuropathic pain following spinal injury,<ref>{{ClinicalTrialsGov| NCT01748695| A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury}}</ref> and spasticity associated with multiple sclerosis. Structure not revealed though Vernalis holds several patents in the area.<ref>{{cite patent | country = US | number = 8450346 | status = granted | title =  Azetidine derivatives as FAAH inhibitors | pubdate = 28 May 2013 | fdate = 27 Feb 2009 | pridate = 4 March 2008 | invent = Roughly S, Walls S, Hart T, Parsons R, Brough P, Graham C, Macias A | assign1 = Vernalis (R&D) Ltd. }}</ref><ref name="pmid22209458">{{cite journal | vauthors = Roughley SD, Browne H, Macias AT, Benwell K, Brooks T, D'Alessandro J, Daniels Z, Dugdale S, Francis G, Gibbons B, Hart T, Haymes T, Kennett G, Lightowler S, Matassova N, Mansell H, Merrett A, Misra A, Padfield A, Parsons R, Pratt R, Robertson A, Simmonite H, Tan K, Walls SB, Wong M | display-authors = 6 | title = Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity | journal = Bioorganic & Medicinal Chemistry Letters | volume = 22 | issue = 2 | pages = 901–6 | date = January 2012 | pmid = 22209458 | doi = 10.1016/j.bmcl.2011.12.032 }}</ref>
{{Div col end}}
{{Div col end}}
=== Inhibition and binding ===
Structural and conformational properties that contribute to enzyme inhibition and substrate binding imply an extended bound conformation, and a role for the presence, position, and [[stereochemistry]] of a [[Fatty acid#Numbering of the carbon atoms in a fatty acid|delta]] [[Cis–trans isomerism|cis]] [[double bond]].<ref>{{cite journal | vauthors = Boger DL, Sato H, Lerner AE, Austin BJ, Patterson JE, Patricelli MP, Cravatt BF | title = Trifluoromethyl ketone inhibitors of fatty acid amide hydrolase: a probe of structural and conformational features contributing to inhibition | journal = Bioorganic & Medicinal Chemistry Letters | volume = 9 | issue = 2 | pages = 265–70 | date = January 1999 | pmid = 10021942 | doi = 10.1016/S0960-894X(98)00734-3 }}</ref>


==Assays==
==Assays==
The enzyme is typically assayed making use of a radiolabelled anandamide [[Substrate (biochemistry)|substrate]], which generates free labelled [[ethanolamine]], although alternative LC-MS methods have also been described.<ref name="pmid20694697">{{cite journal | vauthors = Wang Y, Jones P | title = A scintillation proximity assay for fatty acid amide hydrolase compatible with inhibitor screening | journal = Methods in Molecular Biology (Clifton, N.J.) | volume = 572 | issue =  | pages = 247–59 | year = 2009 | pmid = 20694697 | doi = 10.1007/978-1-60761-244-5_16 | series = Methods in Molecular Biology | isbn = 978-1-60761-243-8 }}</ref><ref name="pmid23044255">{{cite journal | vauthors = Han B, Wright R, Kirchhoff AM, Chester JA, Cooper BR, Davisson VJ, Barker E | title = Quantitative LC-MS/MS analysis of arachidonoyl amino acids in mouse brain with treatment of FAAH inhibitor | journal = Analytical Biochemistry | volume = 432 | issue = 2 | pages = 74–81 | date = January 2013 | pmid = 23044255 | pmc = 3760509 | doi = 10.1016/j.ab.2012.09.031 }}</ref>
The enzyme is typically assayed making use of a radiolabelled anandamide [[Substrate (biochemistry)|substrate]], which generates free labelled [[ethanolamine]], although alternative LC-MS methods have also been described.<ref name="pmid20694697">{{cite journal | vauthors = Wang Y, Jones P | title = A scintillation proximity assay for fatty acid amide hydrolase compatible with inhibitor screening | journal = [[Methods in Molecular Biology]] | volume = 572 | issue =  | pages = 247–59 | year = 2009 | pmid = 20694697 | doi = 10.1007/978-1-60761-244-5_16 | series = Methods in Molecular Biology | isbn = 978-1-60761-243-8 }}</ref><ref name="pmid23044255">{{cite journal | vauthors = Han B, Wright R, Kirchhoff AM, Chester JA, Cooper BR, Davisson VJ, Barker E | title = Quantitative LC-MS/MS analysis of arachidonoyl amino acids in mouse brain with treatment of FAAH inhibitor | journal = Analytical Biochemistry | volume = 432 | issue = 2 | pages = 74–81 | date = January 2013 | pmid = 23044255 | pmc = 3760509 | doi = 10.1016/j.ab.2012.09.031 }}</ref>


== Structures ==
== Structures ==
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* [[Endocannabinoid enhancer]]
* [[Endocannabinoid enhancer]]
* [[Endocannabinoid reuptake inhibitor]]
* [[Endocannabinoid reuptake inhibitor]]
* [[Monoacylglycerol lipase]]
* [[FAAH2]]


== References ==
== References ==

Latest revision as of 02:47, 3 January 2019

"FAAH" redirects here. For other uses, see FAAH (disambiguation).
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Fatty acid amide hydrolase or FAAH (EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993.[1] In humans, it is encoded by the gene FAAH.[2][3][4]

Function

FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[5] In vivo, FAAH is the principal catabolic enzyme for a class of bioactive lipids called the fatty acid amides (FAAs). Members of the FAAs include:

FAAH knockout mice display highly elevated (>15-fold) levels of N-acylethanolamines and N-acyltaurines in various tissues. Because of their significantly elevated anandamide levels, FAAH KOs have an analgesic phenotype, showing reduced pain sensation in the hot plate test, the formalin test, and the tail flick test.[11] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[6]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.[12][13][14]

A mutation in FAAH was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.[15]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders.[15][16][17]

Inhibitors and inactivators

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.[18][19][20][21][22][23][24][25]

Some of the more significant compounds are listed below;

Inhibition and binding

Structural and conformational properties that contribute to enzyme inhibition and substrate binding imply an extended bound conformation, and a role for the presence, position, and stereochemistry of a delta cis double bond.[41]

Assays

The enzyme is typically assayed making use of a radiolabelled anandamide substrate, which generates free labelled ethanolamine, although alternative LC-MS methods have also been described.[42][43]

Structures

The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[4] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[44]

See also

References

  1. ↑ Deutsch DG, Chin SA (September 1993). "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist". Biochemical Pharmacology. 46 (5): 791–6. doi:10.1016/0006-2952(93)90486-G. PMID 8373432.
  2. ↑ Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (November 1996). "Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides". Nature. 384 (6604): 83–7. doi:10.1038/384083a0. PMID 8900284.
  3. ↑ Giang DK, Cravatt BF (March 1997). "Molecular characterization of human and mouse fatty acid amide hydrolases". Proceedings of the National Academy of Sciences of the United States of America. 94 (6): 2238–42. doi:10.1073/pnas.94.6.2238. PMC 20071. PMID 9122178.
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  35. ↑ Clinical trial number NCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" at ClinicalTrials.gov
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  37. ↑ Hart T, Macias AT, Benwell K, Brooks T, D'Alessandro J, Dokurno P, et al. (August 2009). "Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas". Bioorganic & Medicinal Chemistry Letters. 19 (15): 4241–4. doi:10.1016/j.bmcl.2009.05.097. PMID 19515560.
  38. ↑ Clinical trial number NCT01748695 NCT01748695 for " A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury" at ClinicalTrials.gov
  39. ↑ US granted 8450346, "Azetidine derivatives as FAAH inhibitors", published 28 May 2013, assigned to Vernalis (R&D) Ltd. 
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