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Biased Kappa Opioid Agonists as Non-addictive Analgesics

Award Number: R01DA048490
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Biased Kappa Opioid Agonists as Non-addictive Analgesics - Biased Kappa Opioid Agonists as Non-addictive Analgesics. Prescription opioid abuse has increased dramatically over the last decade and now comprises the largest growing substance abuse problem in the United States. These abused medications are mu opioid agonists, and alternatives for pain treatment are needed. Kappa opioid receptor (KOR) agonists are analgesic in humans and have low abuse liability, however the dysphoric and sedating properties of these compounds have precluded their clinical utility and development. Recently several groups have discovered that the analgesic properties are mediated through G- protein signaling, while the sedating and dysphoric effects are mediated through non-G-protein pathways, likely either ßarrestin2 or ERK1/2. Interestingly, several groups have described KOR agonists that preferentially activate G-protein pathways over ßarrestin or ERK1/2 pathways, termed biased KOR agonists. These compounds are promising candidates as non-addictive analgesics that will be devoid of the sedating and dysphoric effects of other typical KOR agonists. We have recently demonstrated that one such compound produces antinociception in mice and rats without evidence of sedation and dysphoria. Further this compound does not interfere with forebrain dopamine neurotransmission, thought to underlie the untoward effects of typical KOR agonists. The extent and nature of signaling bias is determined in vitro, using cell-based assays. As such, it is not readily apparent how this signaling bias in vitro translates into improved pharmacology in vivo. These compounds have been explored as analgesics primarily using non-clinically relevant pain assays, such as tail flick or hot plate tests in rodents, and these assays do not generally predict clinical efficacy. In this application we propose to assess a wide profile of signaling bias for KOR agonists developed using two distinct chemical scaffolds, and to determine the relationship between intracellular signaling bias across multiple pathways in native neuronal tissue (striatum and dorsal root ganglia) with in vivo efficacy in dysregulation of dopamine neurochemistry and production of antinociception, sedation/dysphoria, and abuse liability using clinically relevant rodent models of inflammatory, post-operative, and neuropathic pain, and drug self- administration. Additionally we will assess the role of gender in signaling bias efficacy, as females have been shown to be more sensitive to the analgesic effects of KOR agonists and less sensitive to the dysphoric effects. We hope to determine a profile of signaling bias in vitro that translates into an improved pharmacological profile for KOR agonists in vivo that can be used for further drug development and mechanistic studies.


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: 2025 ( Subtotal = $0 )
2025	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	5	1/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $722,715 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	5	2/15/2023	NON-COMPETING CONTINUATION	$722,715
														Subtotal = $722,715

Issue Date FY: 2022 ( Subtotal = $734,627 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	4	2/18/2022	NON-COMPETING CONTINUATION	$661,162
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	001	4	3/25/2022	NON-COMPETING CONTINUATION	$73,465
														Subtotal = $734,627

Issue Date FY: 2021 ( Subtotal = $741,673 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	3	2/9/2021	NON-COMPETING CONTINUATION	$741,673
														Subtotal = $741,673

Issue Date FY: 2020 ( Subtotal = $755,423 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	2	2/25/2020	NON-COMPETING CONTINUATION	$755,423
														Subtotal = $755,423

Issue Date FY: 2019 ( Subtotal = $479,128 )
2019	2019	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	1	4/15/2019	NEW	$479,128
														Subtotal = $479,128

Grand Total All Awards = $3,433,566

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Biased Kappa Opioid Agonists as Non-addictive Analgesics

Award Number: R01DA048490

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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