Background: Currently, the most dynamic areas in the glutamate receptor system neurobiology are the identification and development of positive allosteric modulators (PAMs) of glutamate ionotropic receptors. PAM-based drugs are of great interest as promising candidates for the treatment of neurological diseases, such as epilepsy, Alzheimer's disease, schizophrenia, etc. Understanding the molecular mechanisms underlying the biological action of natural and synthetic PAMs is a key point for modifying the original chemical compounds as well as for new drug design.

Objective: We are trying to elaborate a system of molecular functional screening of ionotropic glutamate receptor probable PAMs.

Methods: The system will be based on the radioligand - receptor method of analysis and will allow rapid quantification of new AMPAR probable PAMs molecular activity. We plan to use a tritiumlabeled analogue of recently elaborated ionotropic GluR probable PAM ([3H]PAM-43) as the main radioligand.

Results: Here, we characterized the specific binding of the ligand and its ability to potentiate ionotropic GluR currents. The existence of at least two different sites of [3H]PAM-43 specific binding has been shown. One of the above sites is glutamate-dependent and is characterized by higher affinity. “Patchclamp” technique showed the ability of PAM-43 to potentiate ionotropic GluR currents in rat cerebellar Purkinje neurons in a concentration-dependent manner.

Conclusion: The possibility of using PAM-43 as a model compound to study different allosteric effects of potential regulatory drugs (AMPAR allosteric regulators) was shown. [3H]PAM-43 based screening system will allow rapid selection of new AMPAR probable PAM structures and quantification of their molecular activity.

背景：目前，谷氨酸受体系统神经生物学中最活跃的领域是谷氨酸离子型受体的正变构调节剂（PAM）的鉴定和发展。基于PAM的药物作为治疗神经系统疾病（例如癫痫，阿尔茨海默氏病，精神分裂症等）的有前途的候选物而引起了极大的兴趣。了解天然和合成PAM的生物学作用的分子机制是修饰原始PAM的关键点。化合物以及新药设计。

目的：我们正在尝试建立离子型谷氨酸受体可能的PAM的分子功能筛选系统。

方法：该系统将基于放射性配体-受体的分析方法，并将允许快速定量新的AMPAR可能的PAM分子活性。我们计划使用最近拟定的离子型GluR可能的PAM（[3H] PAM-43）的a标记类似物作为主要放射性配体。

结果：在这里，我们表征了配体的特异性结合及其增强离子型GluR电流的能力。已经显示[3H] PAM-43特异性结合的至少两个不同位点的存在。上述位点之一是谷氨酸依赖性的，并具有较高的亲和力。“膜片钳”技术显示了PAM-43能够以浓度依赖的方式增强大鼠小脑浦肯野神经元的离子型GluR电流。

结论：显示了使用PAM-43作为模型化合物研究潜在调节药物（AMPAR变构调节剂）的不同变构作用的可能性。基于[3H] PAM-43的筛选系统将允许快速选择新的AMPAR可能的PAM结构并对其分子活性进行定量。