Inhibitors of arachidonoyl ethanolamide hydrolysis
Arachidonoyl ethanolamide (anandamide) is a naturally occurring brain constituent that binds to a specific brain cannabinoid receptor (CBR1). An amidase activity (anandamide amidase) in membrane fractions of brain and in cultured neuroblastoma cells rapidly degrades anandamide to arachidonic acid (D...
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| Veröffentlicht in: | The Journal of biological chemistry 1994-09, Vol.269 (37), p.22937-22940 |
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| container_title | The Journal of biological chemistry |
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| creator | Koutek, B Prestwich, G D Howlett, A C Chin, S A Salehani, D Akhavan, N Deutsch, D G |
| description | Arachidonoyl ethanolamide (anandamide) is a naturally occurring brain constituent that binds to a specific brain cannabinoid
receptor (CBR1). An amidase activity (anandamide amidase) in membrane fractions of brain and in cultured neuroblastoma cells
rapidly degrades anandamide to arachidonic acid (Deutsch, D. G., and Chin, S. (1993) Biochem. Pharmacol. 46, 791-796). In
the current study, analogs of anandamide representing three classes of putative transition-state inhibitor (trifluoromethyl
ketones, alpha-keto esters, and alpha-keto amides) were synthesized and tested as inhibitors of anandamide hydrolysis in vitro
and as ligands for CBR1. The trifluoromethyl ketones and alpha-keto esters showed nearly 100% inhibition of anandamide hydrolysis
in vitro at 7.5 microM inhibitor and 27.7 microM anandamide. Arachidonyl trifluoromethyl ketone was the only synthetic compound
in the series of fatty acid derivatives able to displace [3H]CP-55940 binding to CBR1 with a Ki of 0.65 microM. It was also
the most effective inhibitor in intact neuroblastoma cells, leading to a 12-fold increase of cellular anandamide levels at
12 microM. From the action of these inhibitors on this hydrolytic enzyme, it seems likely that anandamide is cleaved by a
mechanism that involves an active-site serine hydroxyl group. These inhibitors may serve as useful tools to elucidate the
role anandamide plays in vivo. |
| doi_str_mv | 10.1016/S0021-9258(17)31599-5 |
| format | Article |
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receptor (CBR1). An amidase activity (anandamide amidase) in membrane fractions of brain and in cultured neuroblastoma cells
rapidly degrades anandamide to arachidonic acid (Deutsch, D. G., and Chin, S. (1993) Biochem. Pharmacol. 46, 791-796). In
the current study, analogs of anandamide representing three classes of putative transition-state inhibitor (trifluoromethyl
ketones, alpha-keto esters, and alpha-keto amides) were synthesized and tested as inhibitors of anandamide hydrolysis in vitro
and as ligands for CBR1. The trifluoromethyl ketones and alpha-keto esters showed nearly 100% inhibition of anandamide hydrolysis
in vitro at 7.5 microM inhibitor and 27.7 microM anandamide. Arachidonyl trifluoromethyl ketone was the only synthetic compound
in the series of fatty acid derivatives able to displace [3H]CP-55940 binding to CBR1 with a Ki of 0.65 microM. It was also
the most effective inhibitor in intact neuroblastoma cells, leading to a 12-fold increase of cellular anandamide levels at
12 microM. From the action of these inhibitors on this hydrolytic enzyme, it seems likely that anandamide is cleaved by a
mechanism that involves an active-site serine hydroxyl group. These inhibitors may serve as useful tools to elucidate the
role anandamide plays in vivo.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1016/S0021-9258(17)31599-5</identifier><identifier>PMID: 8083191</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Amidohydrolases - antagonists & inhibitors ; Animals ; Arachidonic Acids - chemical synthesis ; Arachidonic Acids - metabolism ; Binding, Competitive ; Cannabinoids - metabolism ; Cyclohexanols - metabolism ; Endocannabinoids ; Esters - metabolism ; Fatty Acids - metabolism ; Hydrolysis - drug effects ; Ketones - metabolism ; Polyunsaturated Alkamides ; Rats ; Tumor Cells, Cultured</subject><ispartof>The Journal of biological chemistry, 1994-09, Vol.269 (37), p.22937-22940</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c380t-bcaa4c78d862fb31514d71f156878c09b86a2fcc02e7ee04eefc7e6a7aff3abe3</citedby><cites>FETCH-LOGICAL-c380t-bcaa4c78d862fb31514d71f156878c09b86a2fcc02e7ee04eefc7e6a7aff3abe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8083191$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koutek, B</creatorcontrib><creatorcontrib>Prestwich, G D</creatorcontrib><creatorcontrib>Howlett, A C</creatorcontrib><creatorcontrib>Chin, S A</creatorcontrib><creatorcontrib>Salehani, D</creatorcontrib><creatorcontrib>Akhavan, N</creatorcontrib><creatorcontrib>Deutsch, D G</creatorcontrib><title>Inhibitors of arachidonoyl ethanolamide hydrolysis</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Arachidonoyl ethanolamide (anandamide) is a naturally occurring brain constituent that binds to a specific brain cannabinoid
receptor (CBR1). An amidase activity (anandamide amidase) in membrane fractions of brain and in cultured neuroblastoma cells
rapidly degrades anandamide to arachidonic acid (Deutsch, D. G., and Chin, S. (1993) Biochem. Pharmacol. 46, 791-796). In
the current study, analogs of anandamide representing three classes of putative transition-state inhibitor (trifluoromethyl
ketones, alpha-keto esters, and alpha-keto amides) were synthesized and tested as inhibitors of anandamide hydrolysis in vitro
and as ligands for CBR1. The trifluoromethyl ketones and alpha-keto esters showed nearly 100% inhibition of anandamide hydrolysis
in vitro at 7.5 microM inhibitor and 27.7 microM anandamide. Arachidonyl trifluoromethyl ketone was the only synthetic compound
in the series of fatty acid derivatives able to displace [3H]CP-55940 binding to CBR1 with a Ki of 0.65 microM. It was also
the most effective inhibitor in intact neuroblastoma cells, leading to a 12-fold increase of cellular anandamide levels at
12 microM. From the action of these inhibitors on this hydrolytic enzyme, it seems likely that anandamide is cleaved by a
mechanism that involves an active-site serine hydroxyl group. These inhibitors may serve as useful tools to elucidate the
role anandamide plays in vivo.</description><subject>Amidohydrolases - antagonists & inhibitors</subject><subject>Animals</subject><subject>Arachidonic Acids - chemical synthesis</subject><subject>Arachidonic Acids - metabolism</subject><subject>Binding, Competitive</subject><subject>Cannabinoids - metabolism</subject><subject>Cyclohexanols - metabolism</subject><subject>Endocannabinoids</subject><subject>Esters - metabolism</subject><subject>Fatty Acids - metabolism</subject><subject>Hydrolysis - drug effects</subject><subject>Ketones - metabolism</subject><subject>Polyunsaturated Alkamides</subject><subject>Rats</subject><subject>Tumor Cells, Cultured</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1PwzAMhiMEGmPwEybtgBAcCnHSNukRTXxMmsQBkLhFaerQoLYZSSe0f0_3ofnig5_Xth5CpkDvgUL-8E4pg6RgmbwFccchK4okOyFjoJInPIOvUzI-IufkIsYfOlRawIiM5ABBAWPCFl3tStf7EGfeznTQpnaV7_ymmWFf6843unUVzupNFXyziS5ekjOrm4hXhz4hn89PH_PXZPn2spg_LhPDJe2T0midGiErmTNbDv9BWgmwkOVSSEOLUuaaWWMoQ4FIU0RrBOZaaGu5LpFPyM1-7yr43zXGXrUuGmwa3aFfRyVyQYHTdACzPWiCjzGgVavgWh02CqjaulI7V2orQoFQO1cqG3LTw4F12WJ1TB3kDPPr_bx23_WfC6hK502NrWJ5obhQjBVc8H-4MHGm</recordid><startdate>19940916</startdate><enddate>19940916</enddate><creator>Koutek, B</creator><creator>Prestwich, G D</creator><creator>Howlett, A C</creator><creator>Chin, S A</creator><creator>Salehani, D</creator><creator>Akhavan, N</creator><creator>Deutsch, D G</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>19940916</creationdate><title>Inhibitors of arachidonoyl ethanolamide hydrolysis</title><author>Koutek, B ; Prestwich, G D ; Howlett, A C ; Chin, S A ; Salehani, D ; Akhavan, N ; Deutsch, D G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c380t-bcaa4c78d862fb31514d71f156878c09b86a2fcc02e7ee04eefc7e6a7aff3abe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Amidohydrolases - antagonists & inhibitors</topic><topic>Animals</topic><topic>Arachidonic Acids - chemical synthesis</topic><topic>Arachidonic Acids - metabolism</topic><topic>Binding, Competitive</topic><topic>Cannabinoids - metabolism</topic><topic>Cyclohexanols - metabolism</topic><topic>Endocannabinoids</topic><topic>Esters - metabolism</topic><topic>Fatty Acids - metabolism</topic><topic>Hydrolysis - drug effects</topic><topic>Ketones - metabolism</topic><topic>Polyunsaturated Alkamides</topic><topic>Rats</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Koutek, B</creatorcontrib><creatorcontrib>Prestwich, G D</creatorcontrib><creatorcontrib>Howlett, A C</creatorcontrib><creatorcontrib>Chin, S A</creatorcontrib><creatorcontrib>Salehani, D</creatorcontrib><creatorcontrib>Akhavan, N</creatorcontrib><creatorcontrib>Deutsch, D G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Koutek, B</au><au>Prestwich, G D</au><au>Howlett, A C</au><au>Chin, S A</au><au>Salehani, D</au><au>Akhavan, N</au><au>Deutsch, D G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitors of arachidonoyl ethanolamide hydrolysis</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>1994-09-16</date><risdate>1994</risdate><volume>269</volume><issue>37</issue><spage>22937</spage><epage>22940</epage><pages>22937-22940</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Arachidonoyl ethanolamide (anandamide) is a naturally occurring brain constituent that binds to a specific brain cannabinoid
receptor (CBR1). An amidase activity (anandamide amidase) in membrane fractions of brain and in cultured neuroblastoma cells
rapidly degrades anandamide to arachidonic acid (Deutsch, D. G., and Chin, S. (1993) Biochem. Pharmacol. 46, 791-796). In
the current study, analogs of anandamide representing three classes of putative transition-state inhibitor (trifluoromethyl
ketones, alpha-keto esters, and alpha-keto amides) were synthesized and tested as inhibitors of anandamide hydrolysis in vitro
and as ligands for CBR1. The trifluoromethyl ketones and alpha-keto esters showed nearly 100% inhibition of anandamide hydrolysis
in vitro at 7.5 microM inhibitor and 27.7 microM anandamide. Arachidonyl trifluoromethyl ketone was the only synthetic compound
in the series of fatty acid derivatives able to displace [3H]CP-55940 binding to CBR1 with a Ki of 0.65 microM. It was also
the most effective inhibitor in intact neuroblastoma cells, leading to a 12-fold increase of cellular anandamide levels at
12 microM. From the action of these inhibitors on this hydrolytic enzyme, it seems likely that anandamide is cleaved by a
mechanism that involves an active-site serine hydroxyl group. These inhibitors may serve as useful tools to elucidate the
role anandamide plays in vivo.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>8083191</pmid><doi>10.1016/S0021-9258(17)31599-5</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of biological chemistry, 1994-09, Vol.269 (37), p.22937-22940 |
| issn | 0021-9258 1083-351X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_76701304 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Amidohydrolases - antagonists & inhibitors Animals Arachidonic Acids - chemical synthesis Arachidonic Acids - metabolism Binding, Competitive Cannabinoids - metabolism Cyclohexanols - metabolism Endocannabinoids Esters - metabolism Fatty Acids - metabolism Hydrolysis - drug effects Ketones - metabolism Polyunsaturated Alkamides Rats Tumor Cells, Cultured |
| title | Inhibitors of arachidonoyl ethanolamide hydrolysis |
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