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Synthesis and Evaluation of Functionally Biased Opioid Analgesics

Award Number: R01DA033073
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2012
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Synthesis and Evaluation of Functionally Biased Opioid Analgesics - Opiate analgesics act at the mu opioid receptor (MOR) in humans to alleviate pain but also to produce unwanted effects such as constipation, respiratory suppression/overdose and addiction. The overall potency and efficacy of an agonist at the receptor may be determined not only by how well the drug binds the receptor but also by how well the receptor engages with intracellular signaling proteins, such as barrestin2. Our studies over the last decade have led us to hypothesize that if a drug could activate the MOR yet not induce barrestin2 interactions with the receptor, then such a drug might be an efficacious analgesic with limited side effects, producing less tolerance, constipation and overdose potential. In the last 5 years, we have generated more than 50 new MOR agonists that activate G protein signaling pathways in a highly biased manner, such that they do not recruit barrestins. Using these compounds, we have tested our hypothesis and have found that this is approach will allow for the separation of analgesic efficacy in vivo from respiratory suppression. We have identified lead candidates and have filed for patent protection of this series of compounds and are currently pursuing clinical development. While certain physiological side effects have been limited, there is no indication thus far that the compounds will not produce reward or be subject to abuse. In this current proposal, we are seeking to test whether they promote drug preference and to further refine candidate compounds and also to introduce affinity at an additional receptor target as a means to introduce abuse deterrence into the compounds. In our initial screens for target selectivity, we noted some affinity for D3 dopamine receptors in a series that was not further pursued (as we focused on MOR selectivity). However, given that D3 dopamine receptors play an important role in maintaining dopamine homeostasis, can greatly impact drug reward thresholds, and have been identified as a drug abuse deterrence target by NIDA, we will focus on optimizing D3 antagonism while maintaining biased MOR agonism in this compound series. In this multidisciplinary study, the Bohn pharmacology laboratory will work in a highly collaborative manner with the Bannister medicinal chemistry laboratory to generate and optimize multiple derivatives on the compound series (Aim 1). We will use several cell-based assays to characterize the signaling parameters induced by these compounds with the goal of finding opiates that maintain G protein over barrestin signaling bias at MOR yet also display D3 DAR antagonism (Aim 2). These compounds will be tested in mouse models to determine if their signaling properties correlate with their ability to produce analgesia with less respiratory suppression and also if dopaminergic behaviors, such as locomotor activity and conditioned place preference are avoided (Aim 3). Finally, in collaboration with Dr. Michael Cameron of Scripps Florida, we will evaluate the DMPK properties of our best candidate compounds. The information garnered from this proposal will prove useful in the clinical development of pain relievers with limited side effects.


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	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	11	9/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	9	1/3/2023	NON-COMPETING CONTINUATION	-$200,209
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	001	10	1/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$200,209
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $736,212 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	002	11	6/1/2022	NON-COMPETING CONTINUATION	$736,212
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	9	4/11/2022	NON-COMPETING CONTINUATION	-$212,972
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	001	10	4/11/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$212,972
														Subtotal = $736,212

Issue Date FY: 2021 ( Subtotal = $736,212 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	9	4/27/2021	NON-COMPETING CONTINUATION	$736,212
														Subtotal = $736,212

Issue Date FY: 2020 ( Subtotal = $759,012 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	8	5/13/2020	NON-COMPETING CONTINUATION	$736,212
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	001	8	5/18/2020	SUPPLEMENT FOR EXPANSION	$22,800
														Subtotal = $759,012

Issue Date FY: 2019 ( Subtotal = $758,412 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	001	7	6/19/2019	SUPPLEMENT FOR EXPANSION	$22,200
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	7	5/22/2019	NON-COMPETING CONTINUATION	$736,212
														Subtotal = $758,412

Issue Date FY: 2018 ( Subtotal = $732,297 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	001	6	7/18/2018	COMPETING CONTINUATION	$736,212
2018	2016	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	5	2/15/2018	SUPPLEMENT FOR EXPANSION	-$3,915
														Subtotal = $732,297

Issue Date FY: 2016 ( Subtotal = $645,419 )
2016	2016	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	5	5/12/2016	SUPPLEMENT FOR EXPANSION	$15,053
2016	2016	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	5	2/8/2016	EXTENSION WITH OR WITHOUT FUNDS	$630,366
														Subtotal = $645,419

Issue Date FY: 2015 ( Subtotal = $622,873 )
2015	2015	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	4	2/10/2015	NON-COMPETING CONTINUATION	$622,873
														Subtotal = $622,873

Issue Date FY: 2014 ( Subtotal = $644,021 )
2014	2014	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	3	2/26/2014	NON-COMPETING CONTINUATION	$64,404
2014	2014	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	3	1/10/2014	NON-COMPETING CONTINUATION	$579,617
														Subtotal = $644,021

Issue Date FY: 2013 ( Subtotal = $613,852 )
2013	2013	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	2	5/16/2013	NON-COMPETING CONTINUATION	$38,365
2013	2013	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	1/25/2013	NON-COMPETING CONTINUATION	$575,487
														Subtotal = $613,852

Issue Date FY: 2012 ( Subtotal = $634,972 )
2012	2012	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	2/7/2012	NEW	$634,972
														Subtotal = $634,972

Grand Total All Awards = $6,883,282

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Synthesis and Evaluation of Functionally Biased Opioid Analgesics

Award Number: R01DA033073

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2012

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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