title: UCM707, a potent and selective inhibitor of endocannabinoid uptake, potentiates hypokinetic and antinociceptive effects of anandamide.
abstract: To date, UCM707, N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide, has the highest potency and selectivity in vitro as inhibitor of the endocannabinoid transporter, which might make this compound useful in potentiating endocannabinoid transmission, with minimal side-effects, in the treatment of several disorders. However, there is no information about how UCM707 behaves in vivo as regards certain classic effects of endocannabinoids, such as hypomotility and antinociception. In the present work, we tested in rats the dose-response effects of UCM707 in the open-field and hot-plate tests, and, in particular, we analyzed whether this compound enhanced the hypokinetic and/or the antinociceptive actions of anandamide at a subeffective dose, using these two in vivo assays. UCM707, administered alone, had no effect on ambulatory, exploratory and stereotypic activities, time spent in inactivity and sensitivity to noxious heat, with only some small responses at the highest dose used. UCM707, administered at a dose that did not produce any effects by itself or these were very small, was, however, able to significantly potentiate the action of a dose of anandamide that did not produce any effects when it was administered alone. So, the combination of both compounds produced greater decreases in exploratory activity and, particularly in ambulation, increased the time spent in inactivity and the latency to respond to a painful stimulus. In summary, UCM707, as suggested by its in vitro properties, seems also to behave in vivo as a selective and potent inhibitor of the endocannabinoid transporter, showing negligible direct effects on the receptors for endocannabinoids but potentiating the action of these endogenous compounds. This compound is, thus, a promising tool, used alone or in combination with endocannabinoids, for the treatment of a variety of disorders.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: de Lago
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.forename: Silvia
authors.initials: S
authors.lastname: Ortega-Gutiérrez
authors.forename: Alma
authors.initials: A
authors.lastname: Viso
authors.forename: María Luz
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: José A
authors.initials: JA
authors.lastname: Ramos
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D063388:Endocannabinoids; D005106:Exploratory Behavior / Q000187:drug effects; D005663:Furans / Q000494:pharmacology*; D006358:Hot Temperature / Q000009:adverse effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005663:Furans; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D053284:Polyunsaturated Alkamides; C078814:anandamide