High affinity electrophilic and photoactivatable covalent endocannabinoid probes for the CB1 receptor
High affinity electrophilic and photoactivatable covalent endocannabinoid probes for the CB1 receptor
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DOI：
10.1021/jm050272i
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发表时间：
2005-10-06
影响因子：
7.3
通讯作者：
Makriyannis, A
中科院分区：
文献类型：
--
作者：
Li, C;Xu, W;Makriyannis, A
我们已经设计并合成了CB 1受体的前两个高亲和力共价anandamide探针，通过引入亲电子的异硫氰酸根或在花生四烯酸部分的末端碳的可光活化的叠氮基。通过使用环丙基酰胺取代基来优化这些大麻素类似物的头基，以赋予最佳的CB 1亲和力。20-异硫氰酸根合-二十碳-5，8，11，14-四烯酸环丙基酰胺（1，AM3677）和20-叠氮基-二十碳-5，8，11，14-四烯酸环丙基酰胺（2，AM3661）对CB 1受体均表现出高选择性，Ki值分别为1.3和0.9 nM。使用合适的实验条件下，这两种配体被证明共价标记的CB 1受体与高效率。这两个共价探针的内源性大麻素CB 1结合位点打开了大门，探索参与激活的CB 1受体的内源性配体，大麻素的配体结合基序。
We have designed and synthesized the first two high affinity covalent anandamide probes for the CB1 receptor by introducing either an electrophilic isothiocyanato or a photoactivatable azido group at the terminal carbon of the arachidonic acid moiety. The headgroup of these anandamide analogues was optimized by using a cyclopropylamide substituent to impart optimal CB1 affinity. Both 20-isothiocyanato-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (1, AM3677) and 20-azido-eicosa-5,8,11,14-tetraenoic acid cyclopropylamide (2, AM3661) exhibited high selectivities for the CB 1 receptor with K-i values of 1.3 and 0.9 nM, respectively. Using suitable experimental conditions, both ligands were shown to covalently label the CB1 receptor with high efficiency. These two covalent probes for the endocannabinoid CB1 binding site open the door for exploring the ligand binding motifs involved in the activation of the CB1 receptor by its endogenous ligand, anandamide.