Chronic pain is one of the most widespread, debilitating, and highly intricate medical conditions worldwide. Opioid analgesics are the most prescribed pain medication; however, they are highly addictive and have an extensive side-effect profile, including but not limited to nausea, respiratory depression, and euphoria. They exert their effect through binding to the μ-opioid receptor, which is predominantly found in the central and peripheral nervous system (CNS & PNS). In the brain, opioid receptors are present in regions associated with both regulating pain and reward, which has led to a widespread opioid epidemic in the United States and worldwide.<br/><br/>Human Mas-related G protein-coupled receptor X1 (MRGX1) is part of the larger GPCR family of receptors and has restricted expression in nociceptors within the peripheral nervous system. Allosteric activation of Mrgx1 inhibits the high voltage acting Ca<sup>2+</sup> (HVA) channel necessary for nociception. This makes it a promising target for non-addictive pain therapy. Previous efforts in our lab for optimization of hits obtained from high-throughput screening (HTS) has led to the development of a selective MrgX1 allosteric agonist, ML382. This poster will show our SAR studies around ML382 and structural diversification to newer and more potent MrgX1 allosteric agonists. It will also showcase potential pharmacokinetic liabilities of ML382 and our medicinal chemistry-based efforts to overcome these pitfalls using bioisosteres leading to the potential development of a novel non-addictive pain therapy.

Discovery and development of small molecule positive allosteric agonists of Mrgx1 as a potentially novel, non-addictive therapy for chronic pain

ACS Spring Meeting 2021

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