Design, synthesis and biological evaluation of new endocannabinoid transporter inhibitors

• Published in: European journal of medicinal chemistry Vol. 38; no. 4; pp. 403 - 412
• Main Authors: López-Rodrı́guez, Marı́a L., Viso, Alma, Ortega-Gutiérrez, Silvia, Fowler, Christopher J., Tiger, Gunnar, de Lago, Eva, Fernández-Ruiz, Javier, Ramos, José A.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.04.2003; Elsevier
• Subjects: Animals; Arachidonic Acids - antagonists & inhibitors; Arachidonic Acids - chemical synthesis; Arachidonic Acids - chemistry; Arachidonic Acids - metabolism; Arachidonic Acids - pharmacology; Biological and medical sciences; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators - antagonists & inhibitors; Cannabinoid Receptor Modulators - metabolism; Cannabinoids; Cannabinoids - antagonists & inhibitors; Cannabinoids - metabolism; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Endocannabinoid transporter inhibitors; Endocannabinoids; Humans; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Models, Biological; Models, Chemical; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Polyunsaturated Alkamides; Rats; Receptors, Cannabinoid - metabolism; Science & Technology; Structure-Activity Relationship; Structure-affinity relationship studies; U937 Cells; CB 2, cannabinoid receptor subtype 2; EGTA, ethylene glycol-bis(2-aminoethylether)- N, N, N′, N′-tetraacetic acid; BSA, bovine serum albumine; DMAP, N, N-dimethyl-4-aminopyridine; EDTA, ethylenediaminetetraacetic acid; Structure-affinity relationship studies; RTX, resiniferatoxin; FBS, fetal bovine serum; IC 50, compound concentration which cause a 50% of maximal attainable inhibition of the parameter under investigation; CB 1, cannabinoid receptor subtype 1; ANT, anandamide transporter; DCC, dicyclohexylcarbodiimide; DMF, N, N-dimethylformamide; Δ 9-THC, (−)-Δ 9-tetrahydrocannabinol; Cannabinoids; PEI, poliethylenimine; FAAH, fatty acid amide hydrolase; VR 1, vanilloid receptor subtype 1; Max. Inh., maximum inhibition; K i, affinity constant; UCM707, (5 Z,8 Z,11 Z,14 Z)- N-(fur-3-ylmethyl)icosa-5,8,11,14-tetraenamide; Endocannabinoid transporter inhibitors; AM404, N-(4-hydroxyphenyl)arachidonamide; CONSTITUENT; SYSTEM; CONTROL SPASTICITY; RECOGNITION; ANALOGS; structure-affinity relationship studies; ANANDAMIDE TRANSPORT; endocannabinoid transporter inhibitors; RELEVANT; INACTIVATION; CANNABINOID RECEPTOR; cannabinoids; LIGAND; Fatty amide; Rat; Biological transport; Furan derivatives; Fatty ester; Selectivity; Cannabinoid; Oxygen heterocycle; Thiophene derivatives; Structure activity relation; Chemical synthesis; Arachidonic acid derivatives; Rodentia; Endogenous substance; In vitro; In vivo; Vertebrata; Sulfur heterocycle; Mammalia; All cis stereoisomer; Animal; Carboxamide; Inhibitor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(03)00045-X

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.