Abstract
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 μM) and selective endocannabinoid uptake inhibitors with very low affinities for either the enzyme fatty acid amide hydrolase (IC 50=30–113 μM) 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, (5 Z,8 Z,11 Z,14 Z)- 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 μM) 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.
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