Synthesis of new glutamate receptor probes: I. Total synthesis of dysiherbaine, a potent glutamate receptor excitotoxin; II. Design and synthesis of dysiherbaine analogues; III. Synthesis and structure-activity relationships of substituted benzothiadiazi

Since it was discovered that the excitatory amino acid L-glutamate activates particular receptors in the brain, many have sought a more thorough understanding of the complex mechanisms and physiological roles of these receptors. Though many approaches have been used to gain a deeper understanding of these receptors. It was proposed that glutamate may bind to receptors in either an extended or folded form, and since then, several glutamates with "frozen" conformations have been discovered to selectively activate or inactivate glutamate receptors. While many non-natural glutamate analogues have been designed and synthesized and confer excellent receptor selectivity and potency, glutamate-like natural products are still among the most selective and potent probes of glutamate receptor used.;Dysiherbaine, a novel glutamate-containing natural product, was recently isolated from the Micronesian sponge Dysidea herbacea. This compound is one of the most potent neurotoxins and receptor selective agonists yet discovered, making it an intriguing and potentially important new pharmacological probe for glutamate receptor research. A total synthesis of this structurally novel amino acid was therefore performed. In addition, the synthesis of the natural product was designed from the standpoint of amenability to analogue preparation, and by applying this approach, a better understanding of the structure-activity relationships for this natural product can be gained.;Glutamate receptors play key roles in many normal and abnormal brain functions, including learning and memory. Many types of compounds are known to cause increased glutamate receptor activity, by several possible mechanisms, which could, in turn, lead to increased neuronal activity, and thus the higher brain functions of learning and memory. One family of compounds, the benzothiadiazides, have been shown to increase neuronal activity. Using the known benzothiadiazides as lead structures, we discovered that a single alkyl substitution leads to a pronounced enhancement in binding and activity compared to the parent compound. The results from a structure-activity relationship study are discussed.