# Novel anti-cocaine D1 partial agonists

> **NIH NIH SC1** · HUNTER COLLEGE · 2020 · $390,000

## Abstract

ABSTRACT
Close to a million people are addicted to or have abused cocaine according to current statistics. Moreover,
there is an extremely high rate of relapse to cocaine use even after several months of abstinence. No
medications are clinically available to treat cocaine addiction.
Preclinical studies including our preliminary data, indicate that dopamine receptor targeting strategies that
feature D1 partial agonism are promising for anti-cocaine medications development. In that regard,
compounds that exhibit selective D1 partial agonism have demonstrated efficacy in cocaine self-administration
and reinstatement behavioral paradigms in animals. However, the available selective D1 partial agonists suffer
from poor pharmacokinetic properties (including oral bioavailability and blood-brain barrier penetrability) which
precludes their clinical translation. The tetrahydroprotoberberine (THPB) chemotype is a novel scaffold from
which to mine selective D1 partial agonists. In this proposal, we will solve the critical need for clinically useful
D1 partial agonists by deploying strategic chemical modifications on the THPB lead compounds identified from
our preliminary studies via parallel optimization of pharmacokinetic properties and D1 partial agonist
pharmacologies.
The long term goal of this proposal is to use the THPB framework to develop novel, bioavailable, selective D1
partial agonists for the treatment of cocaine addiction. We will test the central hypothesis that "The THPB
framework may be structurally manipulated to afford novel, bioavailable and selective D1 partial agonists with
the ability to reduce cocaine craving in rats ". Testing this hypothesis will engage three specific aims entailing
synthesis, in vitro testing and in vivo behavioral assays. In the first specific aim, we will synthesize libraries of
THPB analogues that contain bioisosteric replacements for metabolically labile functional groups in the lead
THPBs, HUN4404 and HUN361. Specific Aim 2 will involve assessment of in vitro ADME properties as well as
affinities and functional activities of the ligands at dopamine receptors via a variety of well-established assays
for such. In Aim 3, compounds from Aim 2 that meet defined criteria for dopamine receptor activity and in vitro
ADME properties will be submitted to an in vivo PK screen. Subsequently, selected compounds will be
evaluated in a battery of behavioral assays relevant to cocaine addiction viz. self-administration and cocaine
reinstatement. We expect to uncover novel D1 partial agonists that will be transformative in the field as novel
in vivo tools and experimental anti-cocaine therapeutics.

## Key facts

- **NIH application ID:** 9920136
- **Project number:** 5SC1DA049961-02
- **Recipient organization:** HUNTER COLLEGE
- **Principal Investigator:** Wayne Wesley Harding
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920136

## Citation

> US National Institutes of Health, RePORTER application 9920136, Novel anti-cocaine D1 partial agonists (5SC1DA049961-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9920136. Licensed CC0.

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