Pharmacological characterization of novel marine toxins

描述，N(由申请人提供)：天然来源的化合物对于阐明谷氨酸受体(GLUR)的功能和分类至关重要。从甘露海绵中提取的兴奋性氨基酸已被证明是表征GluRs的有价值的工具。该项目将确定新脱氢酶(脱氢酶的天然类似物)和MSVIII-19(脱氢酶合成的中间体)在谷氨酸受体上的药理特性。初步实验表明，水解酶类似物选择性地激活KA和AMPA受体，并拮抗KA和AMPA受体(分别为新水解酶和MSVIII-19)。海洋毒素的进一步特征将涉及在包括离子型和代谢型GluR在内的一系列受体上测试化合物。这些化合物的药理学图谱对于确定赋予GluR特异性的结构成分至关重要，KAR亚基与水解酶和类似物结合的同源建模将被用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助于将来对选择性Glur化合物的设计和合成进行修饰。

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.