Novel marine-derived ligands for probing GluR function

描述（由申请人提供）：本研究工作的目标是确定作用于离子型谷氨酸受体的新药理学药物，离子型谷氨酸受体是哺乳动物大脑兴奋性突触传递的主要介质。同时，我们试图了解这些分子如何与其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，可以从海绵中分离和表征与神经和临床相关的神经活性分子。我们先前描述了最有效的促尿氨基酸，但其特征在于，dysiherbaine（DH），这是从海绵提取物纯化。由于其对红藻氨酸受体（KAR）的极高亲和力，DH是一种强效惊厥剂。此外，DH结构的小的修改将其活性从有效的激动剂转换为选择性拮抗剂，这表明DH可以作为模板，从中产生具有独特药理学特征的选择性KAR拮抗剂。这种拮抗剂可能与基础和临床研究相关，因为已经鉴定出很少的选择性KAR拮抗剂，并且具有这种药理学特征的化合物具有治疗疼痛和癫痫的潜在疗效。为了追求这一目标，我们首先将筛选新的DH类似物作为选择性KAR拮抗剂的活性。初步结果表明，合成的立体异构体和其他类似物的dysiherbaine具有多种活性和对红藻氨酸受体的亲和力。将测试具有新亚基选择性的那些拮抗剂对脑切片制备物中突触受体的活性。其次，我们将进行结构-功能研究，以测试特定的假设，不同的KAR亚基和DH相关配体之间的分子相互作用。这些结果将为设计对KAR具有特定药理活性的新合成配体的产生提供信息。第三，我们将分离和表征增强AMPA和KAR电流的生物活性海绵提取物中的活性成分。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中的功效。总之，这些项目的共同目标是鉴定和药理学分析用于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.