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Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology

Award Number: R01DA031927
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2011
PERIOD OF PERFORMANCE END DATE: 09/07/2025

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Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology - Project Summary We propose to develop new kappa opioid receptor (KOR) agonists that have diverse signaling profiles with the goal of correlating cellular signaling properties to favorable properties (antipruritic, anxiolytic and non-sedating) in mice. The KOR is an attractive drug target because drugs that activate KOR do not lead to overdose or addiction. However, drugs that act at KOR have had their own side effects that have hampered their use clinically. These include diuresis, dysphoria and sedation. Our prior work has introduced new probe compounds that raise the possibility that the therapeutic effects may be separated from the side effects. Compound triazole 1.1 is a potent KOR agonist that activates GTPγS binding in cells and in mouse striatum with the same potency and efficacy as a standard KOR agonist, U50,488H. U50,488 is potent and efficacious at inducing KOR activation across several signaling platforms, including βarrestin2 recruitment. However, triazole 1.1 is far less potent in recruiting βarrestin2 recruitment, and has been shown to be a biased agonist at KOR (bias factor >20). We and others have shown that triazole 1.1 produces antinociception and suppresses pruritis in rodents, yet is devoid of sedating and dysphoria-like properties. Others have shown that triazole 1.1 suppresses oxycodone- induced itch in nonhuman primates and decreases oxycodone self-administration in rats. Therefore, we propose that selective, G protein signaling biased KOR agonists may be a means to preserve desirable effects and avoid side effects. This proposal seeks 5 years of support to generate diverse chemical probes in order to test the extent of this correlation (does biased agonism = less side effects). We introduce two new chemical scaffolds to build upon our already extensive structure-activity relationship collection. We will fully characterize the pharmacological properties of the compounds across functionally diverse cell-based assays with of a goal of identifying compounds capable of fine-tuning KOR responsiveness. Cell-based responses will be validated in mouse models assessing locomotor responses, suppressing pruritis (itch response), diuresis, and measures of anxiolytic-like behaviors to determine that compound maintains the pharmacological profiles in vivo. Compounds will also be tested in combination with morphine. Probe compounds that show favorable behavioral profiles will be used to explore differential KOR signaling in mouse striatum and striatal neurons. Our enthusiastic team consists of established medicinal and synthetic chemists, a structural biologist, and an opioid neuropharmacologist (with both molecular and behavioral pharmacology expertise). The development of pharmacological tools across diverse pharmacophores and correlating their properties with in vivo response profiles will provide guiding evidence of the optimal chemical and pharmacological properties required to refine KOR-targeting therapeutics.


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: 2026 ( Subtotal = $723,119 )
2026	2026	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Drug Use and Addiction Research Programs	001	12	3/19/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$723,119
2026	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	11	3/11/2026	COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	002	11	4/8/2026	COMPETING CONTINUATION	$0
														Subtotal = $723,119

Issue Date FY: 2025 ( Subtotal = $807,171 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	11	4/7/2025	COMPETING CONTINUATION	$807,171
														Subtotal = $807,171

Issue Date FY: 2022 ( Subtotal = -$1,944 )
2022	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	10	8/3/2022	NON-COMPETING CONTINUATION	-$1,944
														Subtotal = -$1,944

Issue Date FY: 2020 ( Subtotal = $638,044 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	10	1/28/2020	NON-COMPETING CONTINUATION	$638,044
														Subtotal = $638,044

Issue Date FY: 2019 ( Subtotal = $654,940 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	9	3/8/2019	NON-COMPETING CONTINUATION	$654,940
														Subtotal = $654,940

Issue Date FY: 2018 ( Subtotal = $689,804 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	001	8	4/26/2018	NON-COMPETING CONTINUATION	$67,491
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	8	1/25/2018	NON-COMPETING CONTINUATION	$607,417
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	002	8	5/2/2018	SUPPLEMENT FOR EXPANSION	$14,896
														Subtotal = $689,804

Issue Date FY: 2017 ( Subtotal = $683,984 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	001	7	5/22/2017	NON-COMPETING CONTINUATION	$68,399
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	7	1/18/2017	NON-COMPETING CONTINUATION	$615,585
														Subtotal = $683,984

Issue Date FY: 2016 ( Subtotal = $721,027 )
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	6	2/18/2016	COMPETING CONTINUATION	$721,027
														Subtotal = $721,027

Issue Date FY: 2015 ( Subtotal = $696,122 )
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	5	4/20/2015	NON-COMPETING CONTINUATION	$696,122
														Subtotal = $696,122

Issue Date FY: 2014 ( Subtotal = $707,331 )
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	4	4/17/2014	NON-COMPETING CONTINUATION	$707,331
														Subtotal = $707,331

Issue Date FY: 2013 ( Subtotal = $679,275 )
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	3	4/16/2013	NON-COMPETING CONTINUATION	$636,820
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	3	5/16/2013	NON-COMPETING CONTINUATION	$42,455
														Subtotal = $679,275

Issue Date FY: 2012 ( Subtotal = $707,581 )
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	2	4/2/2012	NON-COMPETING CONTINUATION	$707,581
														Subtotal = $707,581

Issue Date FY: 2011 ( Subtotal = $724,631 )
2011	2011	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	5/24/2011	NEW	$724,631
														Subtotal = $724,631

Grand Total All Awards = $8,431,085

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Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology

Award Number: R01DA031927

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2011

PERIOD OF PERFORMANCE END DATE: 09/07/2025

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