# Pharmacological validation of adenylyl cyclase 1 as a drug target for chronic pain

> **NIH NIH R01** · PURDUE UNIVERSITY · 2024 · $63,436

## Abstract

Chronic pain costs the US more than $635 billion per year, however, patients fail to receive adequate relief
from the available drugs and often become drug-dependent. These observations highlight the importance for
identifying new agents acting on unique targets to treat chronic pain. Genetic, neurobiological, and preclinical
studies have suggested that adenylyl cyclase type 1 (AC1) may provide that new drug target. AC1 knock out
mice (AC1-/-) show reduced or absent inflammatory and neuropathic pain when compared to littermate controls.
Preclinical studies with a small molecule inhibitor of AC1, NB001 revealed that NB001 reduced chronic pain
responses (i.e. inflammatory and neuropathic) in both mice and rats. Similarly, we have recently shown that a
novel AC1 inhibitor, ST034307 also reduced inflammatory pain in a mouse model. These studies are consistent
with the premise that AC1 is a new target for inhibitors of chronic pain. Unfortunately, both NB001 and ST034307
have significant issues and liabilities preventing further development. To that end, we have recently screened a
chemical library collection that allowed us to identify a pyrimidinone scaffold for the development of novel AC1
inhibitors. This scaffold was prioritized for hit-to-lead optimization based on several promising criteria. Preliminary
structure-activity relationship (SAR) studies have revealed for the first time compounds with sub-micromolar
potency at AC1, as well as selectivity versus the closely-related AC8. Further, initial in vivo studies with a more
soluble pyrimidinone benzlamine analog revealed analgesic activity in an animal model of chronic pain. Despite
these promising observations, the inhibitory mechanism is unknown. The effect of chronic treatment with our
lead compounds on cAMP signaling and opioid receptor modulation of AC1 are also unknown. We propose a
molecular pharmacology characterization of our lead inhibitors of AC1 activity under the following Goals: Goal 1
will use site-directed mutagenesis to examine how the regulatory properties (e.g. Ca2+/CaM, Gαs, and forskolin)
influence to the activity of the inhibitors. Goal 2 will establish the pharmacological activity using an in vitro model
to explore the effects of AC1 inhibition on m opioid receptor regulation of cAMP accumulation under both acute
and chronic conditions. The studies will significanlty and rationally expand Aim 2 of the parent R01 providing
insight regarding the potential Ca2+/CaM-dependent and -independent mechanisms for AC1 inhibition. Further,
the studies in Goal 2 will be instrumental in understanding the translational components of the original Aim 3 by
assessing efficacy, tolerance, and dependence using in vitro models.

## Key facts

- **NIH application ID:** 10950976
- **Project number:** 3R01NS119917-04S1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Daniel Patrick Flaherty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $63,436
- **Award type:** 3
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10950976

## Citation

> US National Institutes of Health, RePORTER application 10950976, Pharmacological validation of adenylyl cyclase 1 as a drug target for chronic pain (3R01NS119917-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10950976. Licensed CC0.

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