In vivo pharmacological actions of two novel inhibitors of anandamide cellular uptake.
Two inhibitors of the cellular uptake of the endocannabinoid anandamide, (R)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine and (S)-N-oleoyl-(1'-hydroxybenzyl)-2'-ethanolamine (OMDM-1 and OMDM-2, respectively), were recently synthesized, and their in vitro pharmacological activity described. Here we have assessed their activity in two typical pharmacological responses of cannabimimetic compounds. We first examined whether these compounds exert any effect per se on locomotion and pain perception in rats, and/or enhance the effects of anandamide on these two processes. We compared the effects of the novel compounds with those produced by a previously developed selective inhibitor, N-arachidonoyl-(2-methyl-4-hydroxyphenyl)amine (VDM-11). When assayed alone, OMDM-1 and OMDM-2 (1-10 mg/kg, i.p.) did not affect any of the five motor parameters under investigation, although the former compound exhibited a trend for the inhibition of ambulation, fast movements, and speed in rats. OMDM-2 and, to a lesser extent, VDM-11 (5 mg/kg, i.p.) enhanced the motor-inhibitory effects of a noneffective dose (2 mg/kg, i.p.) of anandamide, while OMDM-1 did not. In a typical test of acute analgesia, OMDM-2 and VDM-11 (1-10 mg/kg, i.p.), but not OMDM-1, significantly enhanced the time spent by rats on a "hot plate." However, the same compounds (5 mg/kg, i.p.) did not enhance the analgesic effect of a subeffective dose (2 mg/kg, i.p.) of anandamide, whereas OMDM-1 exerted a strong trend towards potentiation (P=0.06). We next explored the possible use of the two novel compounds in a pathological condition. Thus, we determined if, like other previously developed anandamide reuptake inhibitors, OMDM-1 and OMDM-2 inhibit spasticity in an animal model of multiple sclerosis-the chronic relapsing experimental allergic encephalomyelitis in mice. As previously shown with a higher dose of VDM-11, both novel compounds (5 mg/kg, i.v.) significantly reduced spasticity of the hindlimb in mice with chronic relapsing experimental allergic encephalomyelitis. We suggest that OMDM-1 and, particularly, OMDM-2 are useful pharmacological tools for the study of the (patho)physiological role of the anandamide cellular uptake process, and represent unique templates for the development of new antispastic drugs.
de Lago
Eva
E
Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Ciudad Universitaria s/n, Madrid 28040, Spain.
Ligresti
Alessia
A
Ortar
Giorgio
G
Morera
Enrico
E
Cabranes
Ana
A
Pryce
Gareth
G
Bifulco
Maurizio
M
Baker
David
D
Fernandez-Ruiz
Javier
J
Di Marzo
Vincenzo
V
D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D063388:Endocannabinoids; D008297:Male; D051379:Mice; D038602:Mice, Biozzi; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar
D001095:Arachidonic Acids; D001593:Benzyl Compounds; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; C474344:OMDM-1 cpd; C474343:OMDM-2 cpd; D053284:Polyunsaturated Alkamides; C078814:anandamide