PROJECT SUMMARY/ABSTRACT Neuropathic pain (NeuP) affects 6-8% in the adult population. It leads to substantial functional impairment and has deleterious impact on patients’ quality of life. Patients with NeuP continue to have inadequate response to currently available pharmacotherapy options, with less than 25% achieving meaningful improvement. Moreover, major safety concerns are associated with the use of analgesics such as opioids. There is clearly an unmet need for new effective and safe approaches for treating neuropathic pain. 5-HT3 receptors have emerged as a promising target in NeuP. Studies demonstrated that local intrathecal delivery of 5-HT3 antagonists such as ondansetron alleviates mechanical and thermal hypersensitivity in animal models of nerve injury. These compounds target 5-HT3 receptors in the CNS, which are overexpressed after nerve injury, contributing to pain facilitation. The major challenge in achieving efficacy with systemic administration of currently available 5-HT3 antagonists is P-glycoprotein (Pgp)-mediated efflux that limits their penetration to the CNS, and consequently limits their therapeutic effect in NeuP. With adequate CNS penetration, these drugs are expected to be efficacious in relieving NeuP. We hypothesize that identification of CNS-active lead candidates combined with the current understanding of mechanisms of 5-HT3 receptor inhibition gained from recent structural studies and using state-of-the-art computational drug design approaches, will allow the design/development of novel 5-HT3 antagonists with CNS activity and competitive intellectual property (IP) position. The goal of this R61 planning grant is to establish a multidisciplinary and collaborative team of scientists in medicinal and computational chemistry, structural biology, pharmacology, pharmacokinetics, pain biology and clinical/translational pain research to develop and characterize lead candidates and establish the models and feasibility of determining their preclinical efficacy in models of neuropathic pain. We will use molecular dynamics simulations, structure-based virtual screening and drug design to identify and synthesize novel lead 5-HT3 antagonists (Aim 1), characterize in vitro pharmacology and in vivo pharmacokinetics of the novel ligands (Aim 2), and determine the analgesic efficacy and abuse liability of these ligands in rodent models (Aim 3). We expect to establish the multidisciplinary team and its workflow for drug development and characterization, to generate the initial data for novel CNS-penetrant 5-HT3 antagonist development in the subsequent U19 or UG3/UH3 grant mechanism.

PROJECT NARRATIVE Neuropathic pain is a debilitating chronic pain condition that affects 6-8% of adults, the majority of whom do not adequately respond to currently available treatment options. We aim to establish a multidisciplinary team of scientists with expertise in pain biology, medicinal and computational chemistry, structural biology, pharmacology, pharmacokinetics, and translational pain research, and create the appropriate infrastructure for the development of novel non-opioid, 5-HT3 receptor antagonists for the treatment of neuropathic pain.