Neurotransmitter receptor binding and drug discovery.
Neurotransmitter receptor binding and drug discovery.
复制标题
神经递质受体结合和药物发现。
DOI：
10.1021/jm00366a001
复制
发表时间：
1983
影响因子：
7.3
通讯作者：
Snyder,SH
中科院分区：
文献类型：
--
作者：
Snyder,SH
许多精神和心血管药物影响突触机制，以引起其治疗效果。直到最近，这些领域的药物发现计划与神经递质处置的基础研究没有密切联系，因为药物作用的分子机制尚未阐明。因此，在许多情况下，人们不能开发一种系统的方法来确定新的代理人通过监测在体外的生化行动。药物可以通过几种方式影响神经递质系统。它们可以干扰合成或降解酶，它们可以改变递质的储存或释放，或者它们可以模拟或阻断受体部位神经递质的作用。许多精神和心血管药物作用于受体。因此，采用药物开发的分子策略需要简单的受体识别位点的生化测定。除了烟碱胆碱能受体在无脊椎动物的电器官，没有神经递质受体可以监测在简单的结合范例适用于药物筛选，直到大约10年前。成功地鉴定电鳐电器官中烟碱胆碱能受体依赖于极强的毒素（如~（125）I标记的银环蛇毒素）的可用性，以及电鳐电器官中烟碱胆碱能受体的高密度（约占膜蛋白的20%）。相比之下，我们可以计算出，药物和神经递质受体，如阿片受体，在大脑或心脏中所占的重量不应超过百万分之一。令人惊讶的是，人们可以利用简单的可逆结合药物来标记相对粗糙的脑和其他组织膜的受体位点。这种方法首先成功地应用于阿片受体。1-4此后不久，使用相同的一般策略与适当的配体标记甘氨酸、1 2345 6毒蕈碱胆碱能、6，7 GABA、8，9 β-肾上腺素能。
Many psychotropic and cardiovasculardrugs influence synaptic mechanisms to elicit their therapeutic effects. Until recently, drug discovery programs in these areas were not closely linked to basic research on neurotransmitter disposition, because molecular mechanisms of drug action had not been elucidated. Accordingly, in many cases one could not develop a systematic approach to identify new agents by monitoring in vitro biochemical actions. Drugs can influence neurotransmitter systems in several ways. They may interfere with synthesizing or degrading enzymes, they may alter the storage or release of the transmitter, or they may mimic or block the actions of neurotransmitters at receptor sites. Many psychotropic and cardiovascular drugs act at receptors. Thus, to employ molecular strategies for drug development required simple biochemical assays for receptor recognition sites. With the exception of the nicotinic cholinergic receptor in electric organs of invertebrates, no neurotransmitter receptor could be monitored in simple binding paradigms applicable for drug screening until about 10 years ago. Successful characterization of nicotinic cholinergic re-ceptors in electric organs was dependent on the availability of extremely potent toxins, such as-bungarotoxin labeled with 125I, as well as the high density of nicotinic cholinergic receptors, almost 20% of membrane protein in the electric organ of Torpedomarmorata. By contrast, one could calculate that drug and neurotransmitter receptors, such as the opiate receptor, should constitute no more than about one-millionth by weight of brain or heart. It came as something of a surprise, then, that one could utilize simple reversibly binding drugs to label receptor sites in relatively crude preparations of membranes from brain and other tissues. This approach was first applied successfully with the opiate receptor. 1-4 Soon thereafter the same general strategy was used with appropriate ligands to label glycine, 1 2345 6muscarinic cholinergic, 6, 7 GABA, 8, 9 ß-adrenerg-