Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor
Fatty acid sulfonyl fluorides inhibit anandamide metabolism and bind to the cannabinoid receptor
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DOI：
10.1006/bbrc.1997.6072
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发表时间：
1997-02-03
影响因子：
3.1
通讯作者：
Makriyannis, A
中科院分区：
文献类型：
--
作者：
Deutsch, DG;Lin, S;Makriyannis, A
花生四烯酰乙醇胺（anandamide）是大麻素受体（CB 1、CB 2）的内源性配体，也是一种推定的神经递质。苯甲基磺酰氟（PMSF）是一种酶（酰胺酶）的抑制剂，该酶将花生四烯酸水解为花生四烯酸和乙醇胺。我们在这里报告，脂肪酸磺酰氟是花生四烯酸代谢的有效抑制剂。为了研究这些大麻素酰胺酶抑制剂的SAR，我们测试了一系列脂肪酸（C12至C20）磺酰氟，其既作为大麻素降解的抑制剂又作为中枢大麻素受体（CB 1）的配体。AM374（棕榈酰磺酰氟，C16）在防止脑匀浆中花生四烯酸酯水解方面的效力比PMSF高约20倍，比花生四烯酸三氟甲基酮高约50倍。AM374在抑制培养细胞中的酰胺酶方面比PMSF有效一千倍以上。C12至C18磺酰氟类似物作为酰胺酶和逆反应（合酶）的抑制剂是等效的，具有纳摩尔IC 50值。这些化合物通常显示出随着链长增加对CB 1受体的亲和力降低;因此，C12磺酰氟的IC 50为18 nM，C20磺酰氟的IC 50为78 μ M。C14，C16和C18磺酰氟显示出对CB 1受体的酰胺酶的高选择性，因此是潜在有用的选择性花生四烯酸酰胺酶抑制剂。(C)北京：科学出版社.
Arachidonoyl ethanolamide (anandamide) is an endogenous ligand for cannabinoid receptors (CB1, CB2) and a putative neurotransmitter. Phenylmethylsulfonyl fluoride (PMSF) is an inhibitor of the enzyme (an amidase) which hydrolyzes anandamide to arachidonic acid and ethanolamine. We report here that fatty acid sulfonyl fluorides are potent inhibitors of anandamide metabolism. In order to investigate the SAR of these anandamide amidase inhibitors we tested a series of fatty acid (C12 to C20) sulfonyl fluorides both as inhibitors of anandamide degradation and as ligands for the central cannabinoid receptor (CB1). AM374 (palmitylsulfonyl fluoride, C16) was approximately 20 times more potent than PMSF and 50 times more potent than arachidonyltrifluoromethyl ketone in preventing the hydrolysis of anandamide in brain homogenates. AM374 was over a thousand-fold more effective than PMSF in inhibiting the amidase in cultured cells. The C12 to C18 sulfonyl fluoride analogs were equipotent as inhibitors of the amidase and the reverse reaction (the synthase) with nanomolar IC50 values. These compounds generally showed decreasing affinity for the CB1 receptor as the chain length increased; thus, C12 sulfonylfluoride had an IC50 of 18 nM and C20 sulfonylfluoride had an IC50 Of 78 mu M. The C14, C16, and C18 sulfonyl fluorides showed high selectivity for the amidase over the CB1 receptor and thus are potentially useful selective anandamide amidase inhibitors. (C) 1997 Academic Press.