PROJECT SUMMARY/ABSTRACT In the intensive care unit, pulmonary and critical care physicians must often balance between ensuring that their patients have both adequate drive to breathe and adequate analgesia and sedation. Extubation can be difficult in patients with opioid-induced respiratory depression (OIRD), particularly when benzodiazepine anxiolytics are also needed. Healthcare expenditures for prolonged intubation in patients with respiratory depression approach $1 billion annually. Our group is developing a novel class of respiratory stimulants to meet this need. These molecules are safe precursors of the potent respiratory stimulant, S-nitrosocysteine, which engages therapeutic targets in the class of voltage gated potassium channel (Kv) proteins, including Kv 1.1,1.2 and β2. We have two lead compounds that prevent OIRD but do not reverse analgesia in mice, rats and beagles. They also reverse respiratory depression caused by non-narcotic agents. Preliminary market analysis shows that use of respiratory stimulants in this class could prevent many post-operative ICU admissions and, for those patients who do require ICU admission, decrease the time on mechanical ventilation. The net effect will be reduced morbidity, mortality and cost. We also anticipate benefit for patients with advanced heart failure, COPD, cystic fibrosis - diagnoses associated with marginal ventilatory reserve - who require opioid pain management and/or anxiolytics. In this project, we will obtain: 1) more data to help choose a lead compound; 2) a comparison with naloxone (though naloxone is not analgesia-sparing, it is still information that investors want); 3) data with regard to respiratory stimulation during combined treatment with narcotics and benzodiazepines; 4) more data regarding the cellular metabolism; and 5) an optimized business model. With the assistance of our Accelerator partner and Project Manager, additional preliminary comparisons of stability and of Absorption, Distribution, Metabolism and Excretion (ADME) can be made and a pre-IND meeting arranged during the R33 phase. This product class is unique. Its mechanism of action has not previously been described or developed for any drug. It is also uniquely able safely to stimulate respiratory drive without blunting analgesia.