SKF83959 exhibits biochemical agonism by stimulating [35S]GTPγS binding and phosphoinositide hydrolysis in rat and monkey brain
SKF83959 exhibits biochemical agonism by stimulating [35S]GTPγS binding and phosphoinositide hydrolysis in rat and monkey brain
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DOI：
10.1016/s0028-3908(01)00011-9
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发表时间：
2001-05-01
影响因子：
4.7
通讯作者：
Undie, AS
中科院分区：
文献类型：
--
作者：
Panchalingam, S;Undie, AS
SKF83959是一种对胺能受体具有高亲和力的苯扎西平，它能引起啮齿动物的梳理和空腹咀嚼等行为，这些行为是多巴胺D(1)样受体刺激的特征。然而，与经典的D(1)激动剂不同的是，SKF83959不刺激腺酰环化酶。了解到一些D(1)样受体与大脑中磷脂酶C介导的信号级联反应，本研究旨在确定SKF83959是否在生化水平上表现出激动性作用，以及苯扎西平是否以与药物的行为效应相一致的方式调节磷脂酰肌醇的水解。与多巴胺和选择性D(1)样激动剂SKF38393类似，SKF83959以激动剂样的方式竞争性地取代[(3)H]多巴胺的受体结合，显著刺激[(35)S]鸟苷-5‘-O-(3-硫代)三磷酸的结合，并有效地促进磷脂酶C介导的肌醇磷脂在大鼠和猴脑组织中的水解。SKF83959通常比SKF38393更有效，而SKF38393一直表现出更好的药理效果。这些发现可能暗示磷脂酶C信号级联在SKF83959的激动性行为和抗帕金森病活性中起作用。多巴胺敏感的磷脂酶C信号可能应该被考虑在随后的正常或疾病大脑中多巴胺能功能的机制和模型的公式中。(C)2001爱思唯尔科学有限公司。保留所有权利。
SKF83959, a benzazepine with high affinity for aminergic receptors, elicits behaviors such as grooming and vacuous chewing that are characteristic of dopamine D(1)-like receptor stimulation in rodents. Unlike classical D(1) agonists, however, SKF83959 does not stimulate adenylyl cyclase. Knowing that some D(1)-like receptors are coupled to phospholipase C-mediated signaling cascades in the brain, the present study aimed to determine whether SKF83959 exhibits an agonistic action at the biochemical level and also whether this benzazepine can modulate phosphoinositide hydrolysis in a manner that would be consistent with the behavioral effects of the drug. Similar to dopamine and the selective D(1)-like agonist SKF38393, SKF83959 competitively displaced the receptor binding of [(3)H]dopamine in an agonist-like manner, significantly stimulated [(35)S]guanosine-5'-O-(3-thio)triphosphate binding, and potently enhanced phospholipase C-mediated phosphoinositide hydrolysis in rat and monkey brain tissues. SKF83959 was generally more potent than SKF38393, whereas SKF38393 consistently exhibited greater pharmacological efficacy. These findings may implicate a role for the phospholipase C signaling cascade in the agonistic behavioral and antiparkinsonian activity of SKF83959. Dopamine-sensitive phospholipase C signaling should probably be considered in subsequent formulations of mechanisms and models of dopaminergic function in the normal or diseased brain. (C) 2001 Elsevier Science Ltd. All rights reserved.