Project Summary The successful management of chronic pain is inadequate in many patients and has contributed to the abuse of and addiction to opioids, a continuing major public health crisis in the United States and worldwide. The development of non-addictive pain therapeutics can help counter opioid addiction and benefit patients, including those who suffer from neuropathic pain, and in particular diabetic neuropathic pain (DNP). Our project’s goal is to develop a safe, efficacious and non-addictive small-molecule drug that activates Kv7 voltage-gated potassium channels to address overactive neuronal activity in DNP. The first specific aim is discover Kv7 activators that favor Kv7 isoforms altered in DNP and found in dorsal root ganglia, namely the Kv7.2/3 isoforms. Through iterative lead optimization studies on our novel series of Kv7 activators, we are targeting Kv7.2/3 activation with selectivity over both Kv7.4 channels and another off target of other Kv7.2/3 activators, GABAA receptors. This approach is expected to decrease off-target side effects observed with the use of earlier non-biased Kv7 activators including urinary retention (mediated by Kv7.4), and somnolence and dizziness (mediated by enhancement of GABAA receptor function). This phase also includes optimization of absorption, distribution, metabolism, excretion, and toxicity profiles and building correlations between in-vitro activities to in-vivo efficacies in a neuropathic rat DNP model. A second animal model, the L5/L6 spinal nerve constriction model, will also be used to test the ability of candidate compounds to generalize to other forms of neuropathic pain. The second specific aim will be to further characterize two to four advanced compounds by assessing additional pharmacological properties including CYP450 induction/time dependent inhibition and in-vitro safety/selectivity panels. The third aim is to select a candidate for study in non-GLP toxicology and pharmacokinetic studies in rodent and non-rodent species. Specific aims four and five involve completing the studies needed to prepare an Investigational New Drug (IND) application. These studies include Chemical Manufacturing Controls activities such as formulation studies and Good Manufacturing Practices synthesis of drug candidate followed by cardiovascular and safety pharmacology studies, and 28-day Good Lab Practices toxicology studies in two animal species. This screening paradigm is intended to establish a clinic-ready, well-tolerated and widely effective product to treat neuropathic pain.