Design, synthesis and biological evaluation of novel arachidonic acid derivatives as highly potent and selective endocannabinoid transporter inhibitors.
In the present work, we have designed and synthesized a series of arachidonic acid derivatives of general structure I which have been characterized as highly potent and selective inhibitors of anandamide transporter (IC(50) = 24-0.8 microM, K(i) > 1000-5000 nM for CB(1) and CB(2) cannabinoid receptors and vanilloid VR(1) receptor). Among them, N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide deserves special attention as being the most potent endocannabinoid transporter inhibitor (IC(50) = 0.8 microM) described to date.
López-Rodríguez
M L
ML
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain. mluzlr@quim.ucm.es
Viso
A
A
Ortega-Gutiérrez
S
S
Lastres-Becker
I
I
González
S
S
Fernández-Ruiz
J
J
Ramos
J A
JA
D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D015195:Drug Design; D063388:Endocannabinoids; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008566:Membranes; D053284:Polyunsaturated Alkamides; D011869:Radioligand Assay; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D002352:Carrier Proteins; D063388:Endocannabinoids; D005663:Furans; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C078814:anandamide