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

Award Number: R44DA050357
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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An optimized screening platform for identifying and quantifying biased agonists as drugs for the treatment of Opioid Use Disorder - Millions of Americans today have an opioid use disorder (OUD). Millions more misuse opioids, and the crisis continues to grow. The goal of this proposal is to speed the discovery of non-addictive analgesics by providing drug discovery teams with simpler, more robust, more quantitative, assays for agonist bias. Driven by the urgency of the problem we are seeking Fast Track support to create new assay and analytic tools for drug discovery in OUD research. Our goal is to optimize and test new assays for agonist bias at particular receptors that couple to both the Gi and β-arrestin signaling pathway, and create new tools to improve the analysis of structure/activity relationships. There are good reasons to search for biased agonists to the receptors identified in the NIDA “top ten” list of medication development priorities. Biased agonists could activate beneficial signaling pathways while avoiding those that cause adverse effects. Finding these biased agonists is difficult: current assays for detecting bias, while established and validated, suffer from drawbacks that are limiting translatability to animal models and clinical studies. These include entirely different sets of experimental conditions for measuring the different signaling pathways being compared and different time courses of the response being measured. The latter results in time-dependence of the bias measurement which complicates predictions of in vivo efficacy and complicates SAR tables by adding extra variables. Our new assay will simultaneously measure the kinetics of Gi and β-arrestin signaling in living cells. This project will involved creating new tools as well as re-purposing ones we have already developed to study non-OUD drug targets. The assay will be optimized for use on standard fluorescence plate readers, and a data analysis toolbox will be developed to simplify quantification of agonist bias based on kinetic measurements. Phase I will complete the initial validation studies on the NOP opioid receptor, with goal of demonstrating assay reliability and sensitivity milestones. Phase II will optimize the assay for D3 dopamine, CB1 cannabinoid and OPRM1 opioid receptors and develop the analysis toolbox for deployment on standard plate readers and software packages commonly used in drug discovery. In the second half of Phase II, assays with detailed protocols will be ready distribute to researchers who are developing new drugs for OUD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	MONTANA MOLECULAR LLC	366 GALLATIN PARK DR STE A	BOZEMAN	MT	59715	GALLATIN	USA	Drug Use and Addiction Research Programs	000	3	4/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $315,386 )
2022	2022	MONTANA MOLECULAR LLC	366 GALLATIN PARK DR STE A	BOZEMAN	MT	59715	GALLATIN	USA	Drug Use and Addiction Research Programs	000	3	1/28/2022	NON-COMPETING CONTINUATION	$315,386
2022	2019	MONTANA MOLECULAR LLC	366 GALLATIN PARK DR STE A	BOZEMAN	MT	59715	GALLATIN	USA	Drug Use and Addiction Research Programs	001	1	5/20/2022	NEW	$0
														Subtotal = $315,386

Issue Date FY: 2021 ( Subtotal = $482,109 )
2021	2021	MONTANA MOLECULAR LLC	366 GALLATIN PARK DR STE A	BOZEMAN	MT	59715	GALLATIN	USA	Drug Use and Addiction Research Programs	000	2	1/26/2021	EXTENSION WITH OR WITHOUT FUNDS	$482,109
														Subtotal = $482,109

Issue Date FY: 2019 ( Subtotal = $221,097 )
2019	2019	MONTANA MOLECULAR LLC	366 GALLATIN PARK DR STE A	BOZEMAN	MT	59715	GALLATIN	USA	Drug Use and Addiction Research Programs	001	1	9/17/2019	NEW	$0
2019	2019	MONTANA MOLECULAR LLC	366 GALLATIN PARK DR STE A	BOZEMAN	MT	59715	GALLATIN	USA	Drug Use and Addiction Research Programs	000	1	9/16/2019	NEW	$221,097
														Subtotal = $221,097

Grand Total All Awards = $1,018,592

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

Award Number: R44DA050357

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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