Saario Susanna M, Poso Antti, Juvonen Risto O, Järvinen Tomi, Salo-Ahen Outi M H
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
J Med Chem. 2006 Jul 27;49(15):4650-6. doi: 10.1021/jm060394q.
The endocannabinoid system consists of two cannabinoid receptors (CB1 and CB2), endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of the endocannabinoids, including fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). In the present study, virtual screening of MGL inhibitors was performed by utilizing a comparative model of the human MGL enzyme. All hit molecules were tested for their potential MGL inhibitory activity, but no compounds were found capable of inhibiting MGL-like enzymatic activity in rat cerebellar membranes. However, these compounds were also tested for their potential FAAH inhibitory activity and five compounds (2-6) inhibiting FAAH were found with IC50 values between 4 and 44 microM. In addition, the hit molecules from the virtual screening of CB2 receptor ligands (reported previously in Salo et al. J. Med. Chem. 2005, 48, 7166) were also tested in our FAAH assay, and four active compounds (7-10) were found with IC50 values between 0.52 and 22 microM. Additionally, compound 7 inhibited MGL-like enzymatic activity with an IC50 value of 31 microM.
内源性大麻素系统由两种大麻素受体（CB1和CB2）、内源性配体（内源性大麻素）以及参与内源性大麻素代谢的酶组成，包括脂肪酸酰胺水解酶（FAAH）和单酰甘油脂肪酶（MGL）。在本研究中，利用人MGL酶的比较模型进行了MGL抑制剂的虚拟筛选。对所有命中分子进行了潜在的MGL抑制活性测试，但未发现能够抑制大鼠小脑膜中MGL样酶活性的化合物。然而，也对这些化合物的潜在FAAH抑制活性进行了测试，发现有五种抑制FAAH的化合物（2 - 6），其IC50值在4至44微摩尔之间。此外，对先前在Salo等人的《药物化学杂志》2005年第48卷第7166页报道的CB2受体配体虚拟筛选中的命中分子也在我们的FAAH测定中进行了测试，发现有四种活性化合物（7 - 10），其IC50值在0.52至22微摩尔之间。此外，化合物7以31微摩尔的IC50值抑制MGL样酶活性。
