title: Design, synthesis, and biological evaluation of new inhibitors of the endocannabinoid uptake: comparison with effects on fatty acid amidohydrolase.
abstract: A new series of arachidonic acid derivatives were synthesized and evaluated as inhibitors of the endocannabinoid uptake. Most of them are able to inhibit anandamide uptake with IC(50) values in the low micromolar range (IC(50) = 0.8-24 microM). In general, the compounds had only weak effects upon CB(1), CB(2), and VR(1) receptors (K(i) > 1000-10000 nM). In addition, there was no obvious relationship between the abilities of the compounds to affect anandamide uptake and to inhibit anandamide metabolism by fatty acid amidohydrolase (FAAH; IC(50) = 30-113 microM). This indicates that the compounds do not exert their effects secondarily to FAAH inhibition. It is hoped that these compounds, particularly the most potent in this series (compound 5, UCM707, with IC(50) values for anandamide uptake and FAAH of 0.8 and 30 microM, respectively), will provide useful tools for the elucidation of the role of the anandamide transporter system in vivo.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain. mluzlr@quim.ucm.es
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: Alma
authors.initials: A
authors.lastname: Viso
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: Gunnar
authors.initials: G
authors.lastname: Tiger
authors.forename: Eva
authors.initials: E
authors.lastname: de Lago
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.forename: José A
authors.initials: JA
authors.lastname: Ramos
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D063388:Endocannabinoids; D006801:Humans; D066298:In Vitro Techniques; D008566:Membranes; D053284:Polyunsaturated Alkamides; D011869:Radioligand Assay; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000099252:Fatty Acid Amide Hydrolases; C469526:Cnr2 protein, rat; C078814:anandamide