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PTPRD ligands for stimulant and opiate use disorders

Award Number: U01DA047713
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 05/01/2023

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PTPRD ligands for stimulant and opiate use disorders - Summary/abstract: There are no FDA-approved medications for stimulant use disorders. Therapies for opiate use disorders remain suboptimal in ways that are now a focus of national attention. PTPRD (receptor type protein tyrosine phosphatase D) is now supported as a target for development of novel drugs to treat stimulant use disorders by genetic, molecular biologic and pharmacologic evidence in humans and mouse models. Data include: a) multiply-replicated human PTPRD genetic associations (clustered SNPs; 10-8 < p < 10-2) with addiction phenotypes including DSM dependence on opiates and stimulants; b) PTPRD SNP associations with levels of PTPRD expression in postmortem human brain; c) reduced cocaine conditioned place preference (CPP) and cocaine self-administration in mice with 50% reductions in PTPRD expression; d) little human or mouse model evidence for toxicity from reduced PTPRD expression; e) identification of 7-BIA (7-butoxyilludalic acid analog) as a PTPRD ligand that inhibits PTPRD's phosphatase; f) no identified 7-BIA toxicity; g) observations that 7-BIA attenuates both cocaine CPP and well-established cocaine self-administration. Human data supports PTPRD associations with vulnerability to opiate use disorders, though there is presently only preliminary mouse model/pharmacologic support for this association. These exciting results strongly support development of therapeutic PTPRD ligands for stimulant use disorders and studies to seek benefits for opiates. We will thus improve PTPRD ligands, identify effects on opiates and move the best novel, patentable PTPRD ligands toward human studies via i) synthesis of novel PTPRD ligand candidates; ii) testing in vitro activities at PTPRD, related phosphatases and off-target effects. We will seek a) improved potency, b) greater selectivity/few “off target” effects, c) improved solubility, d) improved stability; e) predicted good half-life; f) predicted bioavailability after oral administration and g) predicted ability to cross the blood brain barrier. Selected compounds will be screened in vivo for toxicities from acute then chronic dosing in mice. Improved compounds will be tested in cocaine conditioned place preference and self-administration assays. In tests of opiate reward, we will examine effects of 7-BIA, improved compounds and heterozygous PTPRD knockout. The best compounds active in CPP/self-administration will be tested for biodistributions/ metabolism/stability, aversive or rewarding effects of their own, motor/memory/sensory effects and mouse/rat toxicity and preIND studies. We will thus generate novel, well tolerated and bioavailable PTPRD ligands that display in vitro potency, selectivity and stability, in vivo modulation of cocaine reward and, likely, modulation of opiate reward at doses that provide no significant toxicity. Grand Opportunity support will provide compounds and data to help underpin IND submission, intellectual property protection, pharmaceutical partnerships and progress from novel lead compound to exciting new anti-addiction drug candidates.


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 = -$296,250 )
2025	2021	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE BLDG 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	000	3	10/29/2024	NON-COMPETING CONTINUATION	-$296,250
														Subtotal = -$296,250

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE BLDG 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	000	3	7/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	000	3	11/30/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	000	3	2/1/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $1,833,031 )
2021	2021	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	000	3	2/8/2021	NON-COMPETING CONTINUATION	$1,483,588
2021	2021	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	001	3	7/6/2021	SUPPLEMENT FOR EXPANSION	$349,443
														Subtotal = $1,833,031

Issue Date FY: 2020 ( Subtotal = $1,846,328 )
2020	2020	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	000	2	12/17/2019	NON-COMPETING CONTINUATION	$1,378,147
2020	2020	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	002	2	6/19/2020	SUPPLEMENT FOR EXPANSION	$315,055
2020	2020	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	001	2	2/19/2020	NON-COMPETING CONTINUATION	$153,126
														Subtotal = $1,846,328

Issue Date FY: 2019 ( Subtotal = $1,355,537 )
2019	2019	BIOMEDICAL RESEARCH INSTITUTE OF NEW MEXICO	1501 SAN PEDRO DR SE 14	ALBUQUERQUE	NM	87108	BERNALILLO	USA	Drug Use and Addiction Research Programs	000	1	12/28/2018	NEW	$1,355,537
														Subtotal = $1,355,537

Grand Total All Awards = $4,738,646

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PTPRD ligands for stimulant and opiate use disorders

Award Number: U01DA047713

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 05/01/2023

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