Faculty Collaboration Database

Structure-activity relationships among N-arachidonylethanolamine (Anandamide) head group analogues for the anandamide transporter. J Neurochem 2000 Jun;74(6):2597-606

Date

05/23/2000

Pubmed ID

10820223

DOI

10.1046/j.1471-4159.2000.0742597.x

Scopus ID

2-s2.0-0034070409 (requires institutional sign-in at Scopus site)   134 Citations

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.

Author List

Jarrahian A, Manna S, Edgemond WS, Campbell WB, Hillard CJ

Authors

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adjuvants, Immunologic
Amidohydrolases
Animals
Arachidonic Acids
Binding, Competitive
Biological Transport
Cannabinoid Receptor Modulators
Cannabinoids
Carrier Proteins
Cells, Cultured
Cerebellum
Cyclohexanols
Endocannabinoids
Glycerides
Immunosuppressive Agents
Ligands
Neurons
Polyunsaturated Alkamides
Prosencephalon
Rats
Receptors, Cannabinoid
Receptors, Drug
Structure-Activity Relationship
Tritium