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首页> 外文期刊>Life sciences >THE EFFECTS OF SIGMA LIGANDS ON PROTEIN RELEASE FROM LACRIMAL ACINAR CELLS - A POTENTIAL AGONIST ANTAGONIST ASSAY
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THE EFFECTS OF SIGMA LIGANDS ON PROTEIN RELEASE FROM LACRIMAL ACINAR CELLS - A POTENTIAL AGONIST ANTAGONIST ASSAY

机译：SIGMA配体对泪腺癌细胞蛋白质释放的作用-潜在的激动剂拮抗剂分析

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Sigma (sigma) receptor antagonists have been proposed as leading clinical candidates for use in various psychotic disorders. Prior to clinical testing, it is imperative that a new agent be correctly identified as an antagonist and not an agonist since the latter may worsen the psychosis. For sigma-ligands many behavioral and pharmacological assays have been developed in an attempt to classify agonist/antagonist activity. These assays evaluate a response or a behavior in an animal model that can be related to clinical efficacy. However, is the action by the presumed antagonist a consequence of sigma-receptor activity? Previously we have identified sigma-receptors in acinar cells of the main lacrimal gland of the New Zealand white rabbit and have measured protein release after the addition of various N,N-disubstituted phenylalkylamine derivatives known to be sigma-ligands by receptor binding studies. Although protein release from acinar cells has been attributed to either muscarinic or alpha-adrenergic stimulation, protein release from sigma-receptor stimulation was also confirmed. In the reported studies here, we isolated and incubated acinar cells with varying concentrations of known sigma-ligands and measured protein concentration. A knowledge of the receptor profile for the disubstituted phenylalkylamines permitted experiments to be designed in which various alpha, muscarinic, serotonergic, and dopaminergic antagonists could be added in equimolar concentrations. Under the conditions of these experiments, statistically significant increases in protein release for sigma-ligands could be attributed to stimulation of sigma-receptors. Haloperidol, an apparent sigma-antagonist, caused a statistically significant decrease in protein release and also inhibited protein release when tested with a known sigma-ligand, AF2975 [N,N-dimethyl-2-phenylethylamine]. In this system, stimulation and inhibition of protein release were defined as agonist and antagonist behavior, respectively. Of particular interest were the results for BMY14802 and +/- pentazocine, both of which were found to be agonists. Various antipsychotic and antidepressant drugs were measured for their agonist/antagonist behavior. Because of multireceptors present in acini, their agonist or antagonist behavior could not be attributed solely to interaction with the sigma-receptor unless specific antagonists were added. [References: 21]
机译：已经提出西格玛（sigma）受体拮抗剂是用于各种精神病的主要临床候选药物。在临床测试之前，必须将新药正确识别为拮抗剂而不是激动剂，因为后者可能会使精神病恶化。对于sigma-配体，已经开发了许多行为和药理学测定法，以试图将激动剂/拮抗剂活性分类。这些分析评估了动物模型中可能与临床功效相关的反应或行为。但是，假定拮抗剂的作用是否是σ受体活性的结果？以前，我们已经在新西兰白兔的主要泪腺的腺泡细胞中鉴定出了sigma受体，并通过添加各种N，N-二取代的苯基烷基胺衍生物（通过受体结合研究已知为sigma-配体）来测量蛋白质的释放。尽管从腺泡细胞释放的蛋白质被归因于毒蕈碱或α-肾上腺素刺激，但也证实了从sigma受体刺激释放的蛋白质。在这里报道的研究中，我们分离并孵育了具有不同浓度的已知sigma-配体和测量的蛋白质浓度的腺泡细胞。对二取代苯基烷基胺的受体概况的了解使得可以设计实验，其中可以以等摩尔浓度添加各种α，毒蕈碱，血清素能和多巴胺能拮抗剂。在这些实验的条件下，σ配体的蛋白质释放在统计学上的显着增加可能归因于σ受体的刺激。氟哌啶醇是一种明显的σ-拮抗剂，在用已知的σ-配体AF2975 [N，N-二甲基-2-苯基乙胺]进行测试时，引起蛋白质释放的统计学显着降低，并且还抑制了蛋白质释放。在该系统中，刺激和抑制蛋白释放分别定义为激动剂和拮抗剂行为。特别令人感兴趣的是BMY14802和+/- pentazocine的结果，发现两者都是激动剂。测量了各种抗精神病药和抗抑郁药的激动剂/拮抗剂行为。由于痤疮中存在多种受体，除非添加特定的拮抗剂，否则它们的激动剂或拮抗剂行为不能仅归因于与sigma受体的相互作用。 [参考：21]

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