de Lago Eva, Ligresti Alessia, Ortar Giorgio, Morera Enrico, Cabranes Ana, Pryce Gareth, Bifulco Maurizio, Baker David, Fernandez-Ruiz Javier, Di Marzo Vincenzo
Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Ciudad Universitaria s/n, Madrid 28040, Spain.
Eur J Pharmacol. 2004 Jan 26;484(2-3):249-57. doi: 10.1016/j.ejphar.2003.11.027.
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.
两种内源性大麻素花生四烯乙醇胺细胞摄取抑制剂，即（R）-N-油酰基-（1'-羟基苄基）-2'-乙醇胺和（S）-N-油酰基-（1'-羟基苄基）-2'-乙醇胺（分别为OMDM-1和OMDM-2），最近已被合成，并描述了它们的体外药理活性。在此，我们评估了它们在大麻素模拟化合物的两种典型药理反应中的活性。我们首先研究了这些化合物本身是否对大鼠的运动和疼痛感知有任何影响，以及/或者是否增强花生四烯乙醇胺对这两个过程的作用。我们将这些新化合物的作用与先前开发的一种选择性抑制剂N-花生四烯酰基-（2-甲基-4-羟基苯基）胺（VDM-11）所产生的作用进行了比较。单独检测时，OMDM-1和OMDM-2（1-10毫克/千克，腹腔注射）对所研究的五个运动参数均无影响，尽管前一种化合物在抑制大鼠行走、快速运动和速度方面呈现出一种趋势。OMDM-2以及在较小程度上VDM-11（5毫克/千克，腹腔注射）增强了无效剂量（2毫克/千克，腹腔注射）的花生四烯乙醇胺的运动抑制作用，而OMDM-1则没有。在一项典型的急性镇痛试验中，OMDM-2和VDM-11（1-10毫克/千克，腹腔注射），但不是OMDM-1，显著延长了大鼠在 “热板” 上停留的时间。然而，相同剂量（5毫克/千克，腹腔注射）的这些化合物并没有增强亚有效剂量（2毫克/千克，腹腔注射）的花生四烯乙醇胺的镇痛作用，而OMDM-1则呈现出强烈的增强趋势（P=0.0６）。接下来，我们探讨了这两种新化合物在一种病理状况下的可能用途。因此，我们确定OMDM-1和OMDM-2是否像其他先前开发的花生四烯乙醇胺再摄取抑制剂一样，在多发性硬化症的动物模型——小鼠慢性复发性实验性变应性脑脊髓炎中抑制痉挛。正如先前用较高剂量的VDM-11所表明的那样，这两种新化合物（5毫克/千克，静脉注射）均显著降低了患有慢性复发性实验性变应性脑脊髓炎的小鼠后肢的痉挛程度。我们认为OMDM-1，特别是OMDM-2，是研究花生四烯乙醇胺细胞摄取过程的（病理）生理作用的有用药理工具，并且代表了开发新型抗痉挛药物的独特模板。
