Neurotensin 1 allosteric modulator for the treatment of pain

About This Grant

PROJECT SUMMARY The NIH HEAL Initiative aims to tackle two ongoing health care crises: opioid use disorder and uncontrolled pain. Pharmacological approaches targeting both crises are urgently needed. The neurotensin receptor 1 (NTR1) has been a sought-after target for the treatment of both pain and addiction, but development of balanced NTR1 agonists is precluded by their severe side effects. As a G protein-coupled receptor (GPCR) NTR1 signals through the activation of G proteins and β-arrestins (e.g., Arrb2). Arrb2 attenuates drug reward and suppresses pain via regulation of both GPCRs and non-GPCRs, including the NMDA receptor. We have demonstrated in rodents that SBI-553, a novel Arrb2-biased allosteric modulator (BAM) of NTR1, attenuates opioid reward and the reinforcing effects of psychostimulants without the side effects characteristic of balanced NTR1 signaling. Cryo- EM studies demonstrate that SBI-553 binds at an intracellular allosteric site and acts like a molecular glue, directing signaling to Arrb2 in the presence or absence of agonists. Recently we have shown that NTR1 BAMs produce potent antinociception in rodent models, a finding that builds off previous reports that neurotensin, NTR1’s endogenous ligand provided more potent pain relief than morphine through a mechanism that is independent of opioid receptors. NTR1 BAMs raise nociceptive thresholds in wild-type mice, but not in Ntsr1−/−or Arrb2−/− (knockout) mice, confirming the mechanistic requirement for NTR1 and Arrb2. Local or systemic delivery of NTR1 BAMs reduced hypersensitivity in mouse models of postoperative and neuropathic pain and suppressed excitatory synaptic transmission and NMDAR/ERK signaling in spinal cord nociceptive neurons. Additionally, NTR1 BAMs suppressed C-fiber-induced responses in vivo and action potential firing in mouse and human nociceptive sensory neurons in vitro. Collectively, our findings indicate that NTR1 BAMs are an exciting and novel approach to develop a first-in-class non-opioid drug for the treatment of pain. In this application we outline our plan to optimize and develop such a drug for postoperative pain. In the UG3 stage, we will leverage the structure activity relationships developed around SBI-553 and, through a structure-based design lead optimization process, refine and improve the properties of the leads. Co-structures of leads with NTR1 will be determined through CryoEM, such that the iterative medicinal chemistry, design-make-test cycle is informed by computational predictions using both artificial intelligence and structure-based drug design. In the UH3 phase the objective is to derive advanced leads with excellent in vivo potency in acute inflammatory pain, surgical pain, and chronic neuropathic pain models, outstanding drug-like properties, and no limiting CV or CNS safety risk. In the UH3 phase, the selected clinical candidate will be subjected to a standard battery of required IND-enabling studies, leading to an Investigational New Drug Application (IND). Upon acceptance of the IND, we will conduct a phase I, single ascending dose study in healthy volunteers to assess the safety, tolerability and PK of our clinical candidate.