Presentation Title

Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4

Presentation Type

Oral Presentation

Abstract/Artist Statement

The seven transmembrane(7TM) superfamily, also known as G-protein coupled receptors (GPCR), is one of the largest superfamilies in the human genome. With approximately 30% of marketed drugs targeting the GPCRs, these proteins are among the most successful as therapeutic targets. Within the GPCR receptor family there is a subgroup called the metabotropic glutamate receptors (mGluR). Unlike other GPCRs, mGluRs bind the endogenous ligand glutamate via a large Venus flytrap domain (VFT) to produce a cellular response. There are 8 subtypes within the class of mGluRs (1-8) and are grouped by amino acid sequence similarities Depending on the type of compounds that bind and the mGluR subtype, a different cellular response will result. Compounds that target mGluRs are important for the treatment of a variety of central nervous system (CNS) disorders, as well as cancer. Selectively targeting the VFT domain is difficult due to its high similarity throughout the mGluRs. This difficulty can be overcome by targeting another regulatory region which is located in the 7TM, known as the allosteric site. This presents a more selective target due to less sequence similarity between the mGluR subtypes here, this could lead to fewer off target activity. Our isoxazolo[3,4-d]pyridazinones [3,4-d] compounds were tested and found to have selective activity at mGluR 2 and 4. This selectivity, along with other tests, imply binding may not be at the VFT, but rather at the allosteric site as positive allosteric modulators (PAMs), leading to the selective activity. The mGluR2 subtype is a target for treatment of anxiety and schizophrenia, and successful activation may help to alleviate them. Activation of mGluR4 helps to ease the symptoms of Parkinson’s disease and may even slow progress of the disease. Additionally, both of these receptors have been implicated in the treatment of variety of cancers of the brain and other organs systems, such as giloma, medulloblastoma, or colorectal carcinoma, presenting another target to overcome these diseases. Further modifications of our compounds will be developed to optimize selectivity and activity, by working off a hypothesis based on structural binding to the allosteric site. Our progress on the new synthesis and biological evaluation will be presented here along with future work.

Mentor Name

Nicholas Natale

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Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4

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The seven transmembrane(7TM) superfamily, also known as G-protein coupled receptors (GPCR), is one of the largest superfamilies in the human genome. With approximately 30% of marketed drugs targeting the GPCRs, these proteins are among the most successful as therapeutic targets. Within the GPCR receptor family there is a subgroup called the metabotropic glutamate receptors (mGluR). Unlike other GPCRs, mGluRs bind the endogenous ligand glutamate via a large Venus flytrap domain (VFT) to produce a cellular response. There are 8 subtypes within the class of mGluRs (1-8) and are grouped by amino acid sequence similarities Depending on the type of compounds that bind and the mGluR subtype, a different cellular response will result. Compounds that target mGluRs are important for the treatment of a variety of central nervous system (CNS) disorders, as well as cancer. Selectively targeting the VFT domain is difficult due to its high similarity throughout the mGluRs. This difficulty can be overcome by targeting another regulatory region which is located in the 7TM, known as the allosteric site. This presents a more selective target due to less sequence similarity between the mGluR subtypes here, this could lead to fewer off target activity. Our isoxazolo[3,4-d]pyridazinones [3,4-d] compounds were tested and found to have selective activity at mGluR 2 and 4. This selectivity, along with other tests, imply binding may not be at the VFT, but rather at the allosteric site as positive allosteric modulators (PAMs), leading to the selective activity. The mGluR2 subtype is a target for treatment of anxiety and schizophrenia, and successful activation may help to alleviate them. Activation of mGluR4 helps to ease the symptoms of Parkinson’s disease and may even slow progress of the disease. Additionally, both of these receptors have been implicated in the treatment of variety of cancers of the brain and other organs systems, such as giloma, medulloblastoma, or colorectal carcinoma, presenting another target to overcome these diseases. Further modifications of our compounds will be developed to optimize selectivity and activity, by working off a hypothesis based on structural binding to the allosteric site. Our progress on the new synthesis and biological evaluation will be presented here along with future work.