Design, synthesis and biological evaluation of new endocannabinoid transporter inhibitors

In the present work we describe the synthesis and the in vitro evaluation of a series of arachidonic acid derivatives of general structure I as endocannabinoid transporter inhibitors. In addition, we report the first in vivo studies of the most potent derivative (4, UCM707) within this series. The majority of compounds studied are highly potent (IC(50)=24-0.8 micro M) and selective endocannabinoid uptake inhibitors with very low affinities for either the enzyme fatty acid amide hydrolase (IC(50)=30-113 micro M) or for cannabinoid receptor subtype 1 (CB(1)), cannabinoid receptor subtype 2 (CB(2)) and vanilloid receptor subtype 1 (VR(1)) (K(i)=1000-10000 nM). Among them, (5Z,8Z,11Z,14Z)-N-(fur-3-ylmethyl)icosa-5,8,11,14-tetraenamide (UCM707) behaves as the most potent endocannabinoid transporter inhibitor described to date (IC(50)=0.8 micro M) and exhibits improved potency for the anandamide transporter, high selectivity for CB(1) and VR(1) receptors, and modest selectivity for CB(2). In vivo it enhances the analgesia and hypokinetic effects induced by a subeffective dose of anandamide.