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NOP Receptors in nonhuman primate models of AUD

Award Number: R01AA027556
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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NOP Receptors in nonhuman primate models of AUD - PROJECT SUMMARY. Alcohol use disorder (AUD) persists as a costly public health problem that lacks widely effective medications. The scientific premise of the proposed research is that brain receptors for the nociceptin/orphanin FQ peptide (NOP) are promising targets for new medications, but translational studies in sophisticated nonhuman primate (NHP) models are needed to inform and direct drug development and clinical testing. This premise is based on encouraging data from rodent models and positive preliminary data from our NHP laboratory using buprenorphine and its derivative BU08028, termed a “bifunctional” MOP/NOP agonist because it stimulates both NOP and mu opioid peptide (MOP) receptors. The proposed studies combine a well-characterized, clinically relevant NHP model of chronic ethanol (EtOH) drinking, novel NOP- and MOP/NOP-acting drugs, a translational method of pharmacotherapy assessment and noninvasive brain imaging using positron emission tomography (PET imaging). After being induced to drink EtOH using established procedures, male and female rhesus monkeys will have free access to EtOH; responding to receive food pellets will also be monitored as an index of potential side effects. Specific Aim 1 will determine the effects of buprenorphine and its derivative BU08028, in combination with drugs that selectively stimulate or block MOP or NOP receptors. The results will reveal the relative contribution of MOP and NOP receptor stimulation to the ability of bifunctional agonists to decrease EtOH drinking, indicating the ideal pharmacological profile for a medication. Next (Aim 2), drugs that possess the desired profile will be selected from among a catalog of novel compounds synthesized by Co- Investigator Dr. Stephen Husbands. Candidates will be administered daily for several months and effects on moderate and heavy drinking (6 or 22 hours per day, respectively) will be determined using a translational approach developed by the P.I. We expect to identify a compound that produces prolonged suppression of EtOH drinking without altering food-maintained responding or producing adverse effects. Aim 3 consists of PET imaging studies using the novel radiotracer [11C]NOP-1A that run parallel to Aims 1 and 2. These studies will characterize (1) the influence of basal NOP receptor availability on initial sensitivity to EtOH, (2) the effects of long-term EtOH drinking on NOP receptors, (3) the effects of efficacious treatments on NOP receptor availability, (4) the extent of recovery of NOP receptor availability during abstinence from EtOH and, importantly, (5) sex differences in all these measures. Together, the results of these studies will provide novel, translational data to support the feasibility and efficacy of developing MOP/NOP and NOP-selective agonists as novel AUD pharmacotherapies using translational, clinically relevant NHP models.


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 = $458,202 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	5	5/10/2024	NON-COMPETING CONTINUATION	$458,202
														Subtotal = $458,202

Issue Date FY: 2023 ( Subtotal = $497,573 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	4	4/14/2023	NON-COMPETING CONTINUATION	$497,573
														Subtotal = $497,573

Issue Date FY: 2022 ( Subtotal = $497,573 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	3	4/11/2022	NON-COMPETING CONTINUATION	$497,573
														Subtotal = $497,573

Issue Date FY: 2021 ( Subtotal = $502,638 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	2	4/7/2021	NON-COMPETING CONTINUATION	$502,638
														Subtotal = $502,638

Issue Date FY: 2020 ( Subtotal = $618,732 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	1	7/8/2020	NEW	$618,732
														Subtotal = $618,732

Grand Total All Awards = $2,574,718

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NOP Receptors in nonhuman primate models of AUD

Award Number: R01AA027556

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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