title: Structure-activity relationships among N-arachidonylethanolamine (Anandamide) head group analogues for the anandamide transporter.
abstract: Two putative endocannabinoids, N-arachidonylethanolamine (AEA) and 2-arachidonylglycerol, are inactivated by removal from the extracellular environment by a process that has the features of protein-mediated facilitated diffusion. We have synthesized and studied 22 N-linked analogues of arachidonylamide for the purpose of increasing our understanding of the structural requirements for the binding of ligands to the AEA transporter. We have also determined the affinities of these analogues for both the CB(1) cannabinoid receptor and fatty acid amide hydrolase (FAAH). We have identified several structural features that enhance binding to the AEA transporter in cerebellar granule cells. We have confirmed the findings of others that replacing the ethanolamine head group with 4-hydroxybenzyl results in a high-affinity ligand for the transporter. However, we find that the same molecule is also a competitive inhibitor of FAAH. Similarly, replacement of the ethanolamine of AEA with 3-pyridinyl also results in a high-affinity inhibitor of both the transporter and FAAH. We conclude that the structural requirements for ligand binding to the CB(1) receptor and binding to the transporter are very different; however, the transporter and FAAH share most, but not all, structural requirements.
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, Milwaukee 53226, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jarrahian
authors.forename: S
authors.initials: S
authors.lastname: Manna
authors.forename: W S
authors.initials: WS
authors.lastname: Edgemond
authors.forename: W B
authors.initials: WB
authors.lastname: Campbell
authors.forename: C J
authors.initials: CJ
authors.lastname: Hillard
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000378:metabolism*; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000378:metabolism*; D001667:Binding, Competitive; D001692:Biological Transport; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003511:Cyclohexanols / Q000494:pharmacology; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008024:Ligands; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D053284:Polyunsaturated Alkamides; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000276:Adjuvants, Immunologic; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D002352:Carrier Proteins; D003511:Cyclohexanols; D063388:Endocannabinoids; D005989:Glycerides; D007166:Immunosuppressive Agents; D008024:Ligands; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014316:Tritium; D000099252:Fatty Acid Amide Hydrolases; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; C078814:anandamide