The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs.
The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs.
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DOI：
10.1021/cn500325v
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发表时间：
2015-03-18
影响因子：
5
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Chen X;Choo H;Huang XP;Yang X;Stone O;Roth BL;Jin J
在过去的十年中，出现了两种独立的技术，并被神经科学界广泛采用，用于远程控制神经元活动：光遗传学，利用工程化的通道视紫红质和其他视蛋白，以及化学遗传学，利用工程化的G蛋白偶联受体（设计师药物独家激活的设计师受体（DREADDs））和其他邻苯二甲酸配体-受体对。使用定向分子进化，已经开发了两种类型的源自人毒蕈碱乙酰胆碱受体的DREADD：激活神经元放电的hM 3Dq和抑制神经元放电的hM 4Di。重要的是，这些DREADD不被天然配体乙酰胆碱（ACh）激活，但选择性地被氯氮平N-氧化物（CNO）激活，这是一种对药物惰性的配体。CNO已被广泛用于啮齿动物模型中以激活DREADD，尽管CNO在小鼠中不发生显著的代谢转化，但在人类和豚鼠中，一小部分CNO显然代谢为氯氮平，从而降低了DREADD的转化潜力。为了有效地转化DREADD技术，需要下一代DREADD激动剂，并且需要对DREADD的结构-活性关系（SAR）的透彻理解来开发这样的配体。因此，我们进行了hM 3Dq的第一次SAR研究。我们探索了以CNO为代表的支架的多个区域，确定了有趣的SAR趋势，并发现了几种化合物，它们是非常有效的hM 3Dq激动剂，但不激活天然人M3受体（hM 3）。我们还发现，批准的药物perlapine是一种新的hM 3Dq激动剂，对hM 3Dq的选择性是hM 3的10000倍以上。
Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand–receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure–activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10 000-fold selectivity for hM3Dq over hM3.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
2.9
作者：
Farrell MS;Roth BL
通讯作者：
Roth BL
影响因子：
25
作者：
Bock, Roland;Shin, J. Hoon;Kaplan, Alanna R.;Dobi, Alice;Markey, Eric;Kramer, Paul F.;Gremel, Christina M.;Christensen, Christine H.;Adrover, Martin F.;Alvarez, Veronica A.
通讯作者：
Alvarez, Veronica A.
影响因子：
1.8
作者：
HUNZIKER, F;FISCHER, E;SCHMUTZ, J
通讯作者：
SCHMUTZ, J
影响因子：
25
作者：
Boyden, ES;Zhang, F;Deisseroth, K
通讯作者：
Deisseroth, K