# PTPRD ligands for stimulant and opiate use disorders

> **NIH NIH U01** · BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX · 2021 · $1,483,588

## Abstract

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
pr...

## Key facts

- **NIH application ID:** 10073491
- **Project number:** 5U01DA047713-03
- **Recipient organization:** BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
- **Principal Investigator:** George Richard Uhl
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,483,588
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-05-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073491

## Citation

> US National Institutes of Health, RePORTER application 10073491, PTPRD ligands for stimulant and opiate use disorders (5U01DA047713-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073491. Licensed CC0.

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