Development of negative allosteric modulators at the mu opioid receptor

About This Grant

ABSTRACT Pain is a pervasive problem throughout society. It is estimated that about 105 million American adults are affected by moderate to severe pain. Opiates, such as morphine and fentanyl, have been the preferred treatment for moderate to chronic pain. Unfortunately, diversification and usage of opioids driven by fentanyl and its congeners has led to the opioid epidemic in America which is now reaching crisis levels. In addition to overdose which is lethal about 10% of patients on opiates are at risk of developing opiate use disorders (OUD). Current estimates suggest that ~5.6 million people have OUD and close to ~80k have died each year of opioid overdoses. Current treatments for OUD include buprenorphine and methadone which lack efficacy and are not well tolerated while overdose is treated with intranasal NARCAN® and OPVEE®. Both intranasal naloxone and nalmefeme are effective against counteracting overdose mediated by fentanyl while also leading to withdrawal which can be a physician’s worst nightmare. In addition, it is less clear if orthosteric site antagonists will block overdose to higher potency opioids in the nitazene class or carfentanyl class.Through this phased UG3-UH3 grant we propose to develop negative allosteric modulators (NAM’s) of the mu opioid receptors (MOR) as adjuvants in combination with/without naloxone to treat overdose and OUD while not potentiating the withdrawal mediated by naloxone. Towards this we have identified a first in class NAM named 368 identified from a large DNA encoded library (DEL) encoded library (Nature 2024; 631 (8021): 686-693). 368 modulates naloxone activity in cell lines as well as in vivo in mice. It blocks opioid antinociception as well as respiratory depression while causing less withdrawal when used in conjunction with naloxone supporting our hypothesis that NAM’s will reduce opioid withdrawal over orthosteric site antagonists used alone. In the UG3 preclinical phase of this grant we propose to optimize NAM368 for potency, ADME/PK optimization using structure-based design and focused medicinal chemistry. In addition to NAM368 template we have identified second hit we call HG3 from the DEL screening as well. cryoEM structures of both HG3 as well as 368 have been solved and will guide next generation hit to lead design. Additional DEL screening will continue to identify back-up compounds if optimization of current hits doesn’t lead to viable candidates. Compounds will be screened in a battery of biochemical, cell-based assays for potency and selectivity and eventually in ADME/PK assays both in vitro/in vivo and finally in mouse behavioral assays. The UH3 phase of the application will include CMC scale up, formulation development, pre-clinical toxicology and a full IND-enabling development plan to be carried out by ConfometRx. We have established a strong team of medicinal chemists, pharmacologists, structural biologists with expertise in academia, small biotech as well as big pharma to aid our drug development plan for this proposal to meet our milestones in both phases of this grant application.