Title

Potential treatment of Parkinson and Schizophrenia/anxiety using isoxazolo[3,4-d]pyridazinones selective for mGluR 2 and 4

Presentation Type

Presentation

Abstract

The seven transmembrane superfamily (7TM,or G-protein coupled receptors (GPCRs) is one of the largest superfamilies in the human genome, and with approximately 30% of marketed drugs targeting the 7TMs, this class of proteins is among the most successful among therapeutic targets. Each has a binding site which is called a Venus flytrap domain due to its shape. Through this domain a response can be produced in the cell, and depending on the compound that bindings to it, the response can either be increased or decreased. Within this family there is a group called metabotropic glutamate receptors (mGluR) on which the isoxazolo[3,4-d]pyridazinones compounds that we created were tested and found to have activity at mGluR 4 and 2. Interactions at mGluR4 are important targets for the treatment of Parkinson’s disease. When activated, mGluR4 helps to ease the symptoms of Parkinson’s disease and may even slow progress of the disease. MGluR 2 is a target for anxiety, by helping to alleviate it. The other important aspect of the activity was that the compounds were only active at these receptors and not others and did not have overlap between them. This interaction may imply that the compounds may not be acting at the Venus flytrap domain but rather at another regulatory site, which is more selective. The compounds’ selectivity and activity will be optimized using a structure-based binding to the regulatory site as the working hypothesis. Based on this hypothesis more compounds were created via a new process to try to further access more binding regions in the receptor. Our progress on the new synthesis and biological evaluation will be described.

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Potential treatment of Parkinson and Schizophrenia/anxiety using isoxazolo[3,4-d]pyridazinones selective for mGluR 2 and 4

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The seven transmembrane superfamily (7TM,or G-protein coupled receptors (GPCRs) is one of the largest superfamilies in the human genome, and with approximately 30% of marketed drugs targeting the 7TMs, this class of proteins is among the most successful among therapeutic targets. Each has a binding site which is called a Venus flytrap domain due to its shape. Through this domain a response can be produced in the cell, and depending on the compound that bindings to it, the response can either be increased or decreased. Within this family there is a group called metabotropic glutamate receptors (mGluR) on which the isoxazolo[3,4-d]pyridazinones compounds that we created were tested and found to have activity at mGluR 4 and 2. Interactions at mGluR4 are important targets for the treatment of Parkinson’s disease. When activated, mGluR4 helps to ease the symptoms of Parkinson’s disease and may even slow progress of the disease. MGluR 2 is a target for anxiety, by helping to alleviate it. The other important aspect of the activity was that the compounds were only active at these receptors and not others and did not have overlap between them. This interaction may imply that the compounds may not be acting at the Venus flytrap domain but rather at another regulatory site, which is more selective. The compounds’ selectivity and activity will be optimized using a structure-based binding to the regulatory site as the working hypothesis. Based on this hypothesis more compounds were created via a new process to try to further access more binding regions in the receptor. Our progress on the new synthesis and biological evaluation will be described.