Presentation Title

Isoxazolo[3,4-d]pyridazinones are positive modulators of the 7TM metabotropic glutamate receptors, and selective for subtypes 2 and 4. Providing another potential treatment for central nervous system disorders (anxiety, Parkinson’s, ect) and cancer

Presentation Type

Oral Presentation

Abstract

The seven transmembrane superfamily (7TM), or G-protein coupled receptors (GPCRs), is one of the largest superfamilies in the human genome. With approximately 30% of marketed drugs targeting the 7TMs, these proteins are among the most successful among therapeutic targets. Within 7TMs a subgroup called the metabotropic glutamate receptors (mGluR) exist each of which has a binding site named the Venus flytrap domain (VFT). Unlike other 7TMs, mGluRs act through the VFT to produce a cellular response, depending on the type of compounds that bind, a different response results. 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 of the mGluRs is challenging due its similarity. There is another regulatory region in the 7TM, known as an allosteric site, which is more unique between the each mGluRs and presents a more selective target, which could lead to fewer side effects. Our isoxazolo[3,4-d]pyridazinones compounds were tested and found to have selective activity at mGluR 4 and 2. This selectivity along with other tests imply binding may not be at the VFT, but rather at the allosteric site. Activation of mGluR4 helps to ease the symptoms of Parkinson’s disease and may even slow progress of the disease. The mGluR 2 subtype is a target for treatment of anxiety, often helping to alleviate it. 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. Modifications to our compounds to further optimized selectivity and activity will be by using a structure-based binding to the allosteric site as the working hypothesis. Based on this hypothesis, more compounds will be created 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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Apr 27th, 9:20 AM Apr 27th, 9:35 AM

Isoxazolo[3,4-d]pyridazinones are positive modulators of the 7TM metabotropic glutamate receptors, and selective for subtypes 2 and 4. Providing another potential treatment for central nervous system disorders (anxiety, Parkinson’s, ect) and cancer

UC Ballroom, Pod #1

The seven transmembrane superfamily (7TM), or G-protein coupled receptors (GPCRs), is one of the largest superfamilies in the human genome. With approximately 30% of marketed drugs targeting the 7TMs, these proteins are among the most successful among therapeutic targets. Within 7TMs a subgroup called the metabotropic glutamate receptors (mGluR) exist each of which has a binding site named the Venus flytrap domain (VFT). Unlike other 7TMs, mGluRs act through the VFT to produce a cellular response, depending on the type of compounds that bind, a different response results. 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 of the mGluRs is challenging due its similarity. There is another regulatory region in the 7TM, known as an allosteric site, which is more unique between the each mGluRs and presents a more selective target, which could lead to fewer side effects. Our isoxazolo[3,4-d]pyridazinones compounds were tested and found to have selective activity at mGluR 4 and 2. This selectivity along with other tests imply binding may not be at the VFT, but rather at the allosteric site. Activation of mGluR4 helps to ease the symptoms of Parkinson’s disease and may even slow progress of the disease. The mGluR 2 subtype is a target for treatment of anxiety, often helping to alleviate it. 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. Modifications to our compounds to further optimized selectivity and activity will be by using a structure-based binding to the allosteric site as the working hypothesis. Based on this hypothesis, more compounds will be created to try to further access more binding regions in the receptor. Our progress on the new synthesis and biological evaluation will be described.