Novel marine-derived ligands for probing GluR function

描述（由申请人提供）：本研究的目标是确定作用于嗜离子性谷氨酸受体（哺乳动物大脑兴奋性突触传递的主要介质）的新药理学药物。此外，我们试图了解这些分子如何与它们的靶受体的结合域相互作用，以产生选择性的药理学特征。该研究计划的前提是可以从海洋海绵中分离和表征药理学和临床相关的神经活性分子。我们之前描述了迄今为止最有效的癫痫发作氨基酸，从海绵提取物中纯化的苯酞碱（DH）。DH是一种有效的惊厥药，因为它对盐酸盐受体（KARs）具有极高的亲和力。此外，DH结构的微小修饰将其活性从强效激动剂转变为选择性拮抗剂，这表明DH可以作为模板，从中产生具有独特药理特征的选择性KAR拮抗剂。这些拮抗剂可能与基础和临床研究相关，因为很少有选择性KAR拮抗剂被确定，并且具有这种药理特征的化合物在治疗疼痛和癫痫方面具有潜在的治疗功效。为了实现这一目标，我们首先将筛选新的DH类似物作为选择性KAR拮抗剂。初步结果表明，合成立体异构体和其他类似物对盐酸盐受体具有不同的活性和亲和力。这些具有新型亚基选择性的拮抗剂将在脑切片制剂中对突触受体的活性进行测试。其次，我们将开展结构-功能研究，以验证关于不同KAR亚基与dh相关配体之间分子相互作用的特定假设。这些结果将为新的合成配体的产生提供信息，这些配体设计对卡尔斯具有特定的药理活性。第三，我们将分离和表征生物活性海绵提取物的活性原理，增强AMPA和KAR电流。这种活性类似于目前正在研究的AMPA受体调节剂在预防认知能力下降方面的功效。总之，这些项目的共同目标是鉴定和药理分析治疗神经系统疾病的有治疗前景的分子。

DESCRIPTION (provided by applicant): The goal of this research effort is to identify new pharmacological agents that act on ionotropic glutamate receptors, the primary mediators of excitatory synaptic transmission in the mammalian brain. As well, we seek to understand how such molecules interact with the binding domains of their target receptors to generate selective pharmacological profiles. The research program is based on the premise that pharmacologically and clinically relevant neuroactive molecules can be isolated and characterized from marine sponges. We previously described the most potent seizurogenic amino acid yet characterized, dysiherbaine (DH), which was purified from a marine sponge extract. DH is a potent convulsant by virtue of its extremely high affinity for kainate receptors (KARs). Furthermore, small modifications of the DH structure switched its activity from that of a potent agonist to a selective antagonist, suggesting that DH could serve as template from which to generate selective KAR antagonists with unique pharmacological profiles. Such antagonists could be of relevance to both basic and clinical research, because few selective KAR antagonists have been identified and compounds with this pharmacological profile have potential therapeutic efficacy for treatment of pain and epilepsy. To pursue this goal we first will screen novel analogs of DH for activity as selective KAR antagonists. Preliminary results demonstrate that synthetic stereoisomers and other analogs of dysiherbaine have a variety of activities and affinity profiles on kainate receptors. Those antagonists with novel subunit-selectivity will be tested for activity on synaptic receptors in brain slice preparations. Second, we will carry out structure-function studies to test specific hypotheses regarding the molecular interactions between different KAR subunits and DH-related ligands. The results will inform the generation of new synthetic ligands designed to have particular pharmacological activities on KARs. Third, we will isolate and characterize the active principles in a bioactive sponge extract that potentiates AMPA and KAR currents. This activity is similar to that of AMPA receptor modulators currently under investigation for efficacy in prevention of cognitive decline. In summary, these projects have the shared goal of identification and pharmacological analysis of therapeutically promising molecules for treatment of neurological diseases.