A. Jarrahian et al., Structure-activity relationships among N-arachidonylethanolamine (anandamide) head group analogues for the anandamide transporter, J NEUROCHEM, 74(6), 2000, pp. 2597-2606
Two putative endocannabinoids, N-arachidonylethanolamine (AEA) and 2-arachi
donylglycerol, are inactivated by removal from the extracellular environmen
t by a process that has the features of protein-mediated facilitated diffus
ion. We have synthesized and studied 22 N-linked analogues of arachidonylam
ide for the purpose of increasing our understanding of the structural requi
rements for the binding of ligands to the AEA transporter. We have also det
ermined the affinities of these analogues for both the CB1 cannabinoid rece
ptor and fatty acid amide hydrolase (FAAH). We have identified several stru
ctural features that enhance binding to the AEA transporter in cerebellar g
ranule cells. We have confirmed the findings of others that replacing the e
thanolamine head group with 4-hydroxybenzyl results in a high-affinity liga
nd for the transporter. However, we find that the same molecule is also a c
ompetitive inhibitor of FAAH. Similarly, replacement of the ethanolamine of
AEA with 9-pyridinyl also results in a high-affinity inhibitor of both the
transporter and FAAH. We conclude that the structural requirements for lig
and binding to the CB1 receptor and binding to the transporter are very dif
ferent; however, the transporter and FAAH share most, but not all, structur
al requirements.