An optimized screening platform for identifying and quantifying biased agonists as drugs for the treatment of Opioid Use Disorder

! Project Summary Millions of Americans today have an opioid use disorderOUDMillions more misuse opioidsand the crisis continues to growThe goal of this proposal is to speed the discovery of non addictive analgesics by providing drug discovery teams with simplermore robustmore quantitativeassays for agonist biasDriven by the urgency of the problem we are seeking Fast Track support to create new assay and analytic tools for drug discovery in OUD researchOur goal is to optimize and test new assays for agonist bias at particular receptors that couple to both the Gi andarrestin signaling pathwayand create new tools to improve the analysis of structure activity relationshipsThere are good reasons to search for biased agonists to the receptors identified in the NIDAtop tenlist of medication development prioritiesBiased agonists could activate beneficial signaling pathways while avoiding those that cause adverse effectsFinding these biased agonists is difficultcurrent assays for detecting biaswhile established and validatedsuffer from drawbacks that are limiting translatability to animal models and clinical studiesThese include entirely different sets of experimental conditions for measuring the different signaling pathways being compared and different time courses of the response being measuredThe latter results in time dependence of the bias measurement which complicates predictions of in vivo efficacy and complicates SAR tables by adding extra variablesOur new assay will simultaneously measure the kinetics of Gi andarrestin signaling in living cellsThis project will involved creating new tools as well as re purposing ones we have already developed to study non OUD drug targetsThe assay will be optimized for use on standard fluorescence plate readersand a data analysis toolbox will be developed to simplify quantification of agonist bias based on kinetic measurementsPhase I will complete the initial validation studies on the NOP opioid receptorwith goal of demonstrating assay reliability and sensitivity milestonesPhase II will optimize the assay for DdopamineCBcannabinoid and OPRMopioid receptors and develop the analysis toolbox for deployment on standard plate readers and software packages commonly used in drug discoveryIn the second half of Phase IIassays with detailed protocols will be ready distribute to researchers who are developing new drugs for OUD Project Narrative More thanmillion individuals in the United States have an opioid use disorderOUDThe scope of this crisis is staggeringThis proposal is speed up the search for non addictive opiatesThe goal is to develop optimized assays for drug actions at the NIDAtop tendrug targets that will measure the kinetics of both G protein andarrestin signaling in living cellsThis assay will involve new biological toolsand repurpose othersto produce a simple way to measure agonist bias with unprecedented precisionwww montanamolecular com