# Developing nonmuscle II inhibitors for substance use relapse

> **NIH NIH UH3** · SCRIPPS FLORIDA · 2020 · $90,459

## Abstract

Substance use disorder (SUD), a chronic, relapsing disorder with limited treatment options, costs the US ~$700
billion annually. A few, moderately effective replacement therapies exist for opiate, nicotine and alcohol
dependence. However, no such options exist for stimulant dependence and, further, there are no pharmacotherapies
to prevent or even reduce relapse associated with any drug class. Associations that have formed
during periods of drug use serve as powerful relapse factors by triggering motivation to seek the drug. Recently,
the synaptic actin cytoskeleton, a critical regulator of memory, was identified as a biological target for the
selective disruption of these associations. Indeed, intra-CNS actin depolymerization produces an immediate and
persistent loss of well-established memories associated with the stimulant methamphetamine (METH), without
affecting other types of memories. However, β-actin, the isoform implicated in neuronal plasticity, serves critical
functions throughout the body. Therefore, efforts turned to an upstream regulator of the actin cytoskeleton,
nonmuscle myosin II (NMII), a more selectively expressed molecular motor that promotes synaptic actin
polymerization. All results with direct actin depolymerization have been recapitulated with Blebbistatin, a small
molecule inhibitor of NMIIs. Importantly, a single treatment with Blebbistatin is sufficient to produce a
seemingly permanent loss of METH-associated memories. In addition to its efficacy in animal relapse
models, several properties make Blebbistatin an excellent scaffold for medicinal chemistry. Paramount among
these are the molecule’s small size, selectivity for myosin IIs, high brain penetration, and rapid clearance from
plasma and brain (short-acting is sufficient and reduces unwanted peripheral and central effects). Unfortunately,
Blebbistatin’s activity at cardiac muscle myosin IIs is likely a liability. Optimization efforts have been limited
because the therapeutic potentials of NMII inhibition have only been realized in the past few years. Thus, the
central goal of this proposal is to develop a safe and selective NMII small molecule inhibitor with improved
potency and solubility, that retains its existing, advantageous DMPK properties with minimized toxicological
parameters. To accomplish the overall goal of developing an IND ready compound, an extensive pharmaceutical
approach to drug discovery and development centered on Blebbistatin analogs will be employed, centered on a
detailed structure activity relationship approach. A team has been assembled with many years of preclinical drug
development experience that encompasses all of the methodologies employed in this project (medicinal
chemistry, biochemistry, cell biology, neurobiology, in vivo pharmacology, drug metabolism and
pharmacokinetics (DMPK), toxicology, and clinical research), making this team uniquely qualified to direct the
program. By capitalizing on the unique therapeutic discovery and de...

## Key facts

- **NIH application ID:** 10007910
- **Project number:** 5UH3NS096833-05
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Patrick Robert Griffin
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $90,459
- **Award type:** 5
- **Project period:** 2016-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007910

## Citation

> US National Institutes of Health, RePORTER application 10007910, Developing nonmuscle II inhibitors for substance use relapse (5UH3NS096833-05). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10007910. Licensed CC0.

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