Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Neuropharmacology. 2010 Mar;58(3):640-9. doi: 10.1016/j.neuropharm.2009.11.013. Epub 2009 Dec 4.
Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited approximately 100-fold selectivity for GluK2 over GluK3 subunits, which was attributable to the C8 hydroxyl group in NDH. We used molecular dynamic simulations to determine the specific interactions between NDH and residues within the ligand-binding domains of these two kainate receptor subunits that contribute to the divergent apparent affinities for the compound. These data demonstrate that interactions with the GluK1 subunit are preserved in analogs with substitutions at C10 in NDH and further reveal the determinants of selectivity and pharmacological activity of molecules acting on kainate receptor subunits, which could aid in design of additional compounds that target these receptors.
红藻氨酸受体拮抗剂在多种神经病理学中具有作为治疗剂的潜力。对先前具有惊厥作用的海洋毒素 neodysiherbaine A（NDH）进行的合成修饰产生了一系列具有不同红藻氨酸受体药理学作用的分子。在这里，我们描述了三种新的 NDH 合成类似物，它们在海洋毒素的吡喃环的 C10 位置具有取代基。在使用重组红藻氨酸和 AMPA 受体进行放射性配体置换测定时，类似物表现出对 GluK1（GluR5）亚基的高亲和力结合，并且对 GluK2（GluR6）和 GluK3（GluR7）亚基的亲和力较低。此外，天然毒素 NDH 对 GluK2 相对于 GluK3 亚基的选择性约为 100 倍，这归因于 NDH 中的 C8 羟基。我们使用分子动力学模拟来确定 NDH 与这两个红藻氨酸受体亚基的配体结合域内的残基之间的特定相互作用，这些相互作用导致对该化合物的明显亲和力的差异。这些数据表明，在 NDH 的 C10 取代物的类似物中，与 GluK1 亚基的相互作用得以保留，并且进一步揭示了作用于红藻氨酸受体亚基的分子的选择性和药理学活性的决定因素，这有助于设计针对这些受体的其他化合物。
