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Biasing Mu Opioid Receptor Signaling in vivo

Award Number: R01DA038964
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Biasing Mu Opioid Receptor Signaling in vivo - Summary Prescription opioid narcotics, such as morphine, oxycodone, and fentanyl, produce analgesia and side effects through activation of the mu opioid receptor (MOR), a G protein coupled receptor (GPCR). Our long- standing goal is to understand how MOR signals to produce distinct biological effects and to ultimately influence the development of therapeutics that will take advantage of “good” receptor signaling (pain relief) and avoid “bad” receptor signaling that leads to unwanted opioid side effects like respiratory suppression and tolerance. It has become increasingly evident that different drug structures can elicit different receptor signaling cascades at a single receptor, likely by changing the affinities for association with intracellular binding partners. Over the past decade, we have developed a series of agonists that act in a manner that drives G protein signaling downstream of MOR and induce little interactions between the receptor and arrestin2, a scaffolding protein. Moreover, we have determined that several of these agonists produce antinociception without inducing respiratory suppression. One compound, SR-17108 has been shown to be potent and efficacious in a neuropathic pain model where it performed better than oxycodone or morphine. Chronic treatment with SR-17018 did not lead to tolerance in the mouse models. Extensive biochemical studies have recently revealed that at least 4 agonists from this class, including SR-17018, are binding to different sites on the receptor and are therefore noncompetitive or allosteric agonists. In this proposal, we want to determine if it is this noncompetitive property, or other pharmacological properties that the compounds possess that confer the favorable physiological profiles. Further, we are seeking to determine the binding site of these compounds. Since the compounds bind to different sites on the receptor than conventional opioid drugs, we will ask how the allosteric compounds interact with morphine, fentanyl and naloxone when administered together.


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 = $456,713 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	9	7/17/2025	NON-COMPETING CONTINUATION	$456,713
														Subtotal = $456,713

Issue Date FY: 2024 ( Subtotal = $456,713 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	8	6/17/2024	NON-COMPETING CONTINUATION	$456,713
														Subtotal = $456,713

Issue Date FY: 2023 ( Subtotal = $456,713 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	000	7	6/30/2023	NON-COMPETING CONTINUATION	$456,713
														Subtotal = $456,713

Issue Date FY: 2022 ( Subtotal = $456,713 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Use and Addiction Research Programs	001	6	8/11/2022	COMPETING CONTINUATION	$456,713
2022	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	5	11/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $456,713

Issue Date FY: 2019 ( Subtotal = $480,000 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	5	3/6/2019	NON-COMPETING CONTINUATION	$480,000
														Subtotal = $480,000

Issue Date FY: 2018 ( Subtotal = $480,000 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	001	4	4/26/2018	NON-COMPETING CONTINUATION	$48,000
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	4	3/13/2018	NON-COMPETING CONTINUATION	$432,000
														Subtotal = $480,000

Issue Date FY: 2017 ( Subtotal = $480,000 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	000	3	3/13/2017	NON-COMPETING CONTINUATION	$432,000
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Use and Addiction Research Programs	001	3	5/22/2017	NON-COMPETING CONTINUATION	$48,000
														Subtotal = $480,000

Issue Date FY: 2016 ( Subtotal = $475,200 )
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	2	3/24/2016	NON-COMPETING CONTINUATION	$475,200
														Subtotal = $475,200

Issue Date FY: 2015 ( Subtotal = $480,000 )
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	1	3/19/2015	NEW	$480,000
														Subtotal = $480,000

Grand Total All Awards = $4,222,052

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Biasing Mu Opioid Receptor Signaling in vivo

Award Number: R01DA038964

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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