Pharmacological characterization of novel marine toxins

描述，N（由申请人提供）：天然来源化合物对谷氨酸受体（GluR）功能和分类的阐明至关重要。从海绵体中提取的兴奋性氨基酸，如脱氧麻黄碱（DH），已被证明是表征GluRs的有价值的工具。该项目将确定谷氨酸受体上neoDH （DH的天然类似物）和MSVIII-19 （DH合成中间体）的药理学特征。初步实验表明，DH类似物选择性激活kainite受体，并拮抗KA和AMPA受体（分别为neoDH和MSVIII-19）。海洋毒素的进一步表征将涉及在一系列受体上测试化合物，包括嗜离子性和代谢性GluRs。这些化合物的药理学分析对于确定赋予GluR特异性的结构成分至关重要，KAR亚基与DH和结合的类似物的同源性建模将用于确定对毒素的结合和选择性至关重要的氨基酸残基。这些化合物的性质将有助于未来设计和合成选择性GluR化合物的修饰。

DESCRIPTIO,N (provided by applicant): Natural source compounds have been critical for the elucidation of glutamate receptor (GluR) function and classification. Excitatory amino acids derived from the manne sponges, such as dysiderbaine (DH), have proven to be valuable tools for characterizing GluRs. This project will determine the pharmacological profile of neoDH (a natural analog of DH) and MSVIII-19 (an intermediate of DH synthesis) on glutamate receptors. Preliminary experiments show, analogues of DH activate kainite receptors selectively and antagonize KA and AMPA receptors (neoDH and MSVIII-19, respectively). Further characterization of the marine toxins will involve testing the compounds on an array of receptors including both ionotropic and metabotropic GluRs. Pharmacological profiling of these compounds is critical to determine the structural components that confer GluR specificity in tandem, homology modeling of KAR subunits with DH and the analogs bound will be utilized to determine the amino acid residues critical for the binding and selectivity of the toxins. The characterization of these compounds will facilitate future modification in design and synthesis of selective GluR compounds.