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.
López-Rodríguez
María L
ML
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040, Madrid, Spain. mluzlr@quim.ucm.es
Viso
Alma
A
Ortega-Gutiérrez
Silvia
S
Fowler
Christopher J
CJ
Tiger
Gunnar
G
de Lago
Eva
E
Fernández-Ruiz
Javier
J
Ramos
José A
JA
D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D063388:Endocannabinoids; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D015394:Molecular Structure; D053284:Polyunsaturated Alkamides; D051381:Rats; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013329:Structure-Activity Relationship; D020298:U937 Cells
D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D002352:Carrier Proteins; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; C078814:anandamide