Pharmacological characterization of novel marine toxins

NITIO，N（由申请人提供）：天然来源化合物对于阐明谷氨酸受体（GluR）功能和分类至关重要。 来自人海绵的兴奋性氨基酸，如dysiderbaine（DH），已被证明是表征GluRs的有价值的工具。 该项目将确定neoDH（DH的天然类似物）和MSVIII-19（DH合成的中间体）对谷氨酸受体的药理学特征。 初步实验表明，DH的类似物选择性地激活钾盐镁矾受体并拮抗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，包括离子型和代谢型GluR。 这些化合物的药理学分析对于确定串联赋予GluR特异性的结构组分是至关重要的，将利用KAR亚基与DH和结合的类似物的同源性建模来确定对毒素的结合和选择性至关重要的氨基酸残基。 这些化合物的表征将有利于未来的设计和合成选择性GluR化合物的修改。

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.