# Biased Muscarinic Acetylcholine Receptor Signaling in Obstructive Lung Disease Pathology and Therapy

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $390,000

## Abstract

Project Summary
Clinical management of obstructive lung diseases such as asthma and chronic obstructive pulmonary disease
(COPD) relies heavily of drugs that are either agonist or antagonists of G protein-coupled receptors (GPCRs).
This is because GPCRs control important airway cell functions (contraction, growth, cytokine/chemokine
production, chemotaxis, and permeability) that become dysregulated in disease. Unfortunately, these drugs
have limitations with respect to both efficacy and safety, and many patients experience suboptimal control. We
propose to identify new, more effective ligands that target the M3 muscarinic acetylcholine receptor (M3
mAChR) as a potential COPD therapy, by embracing the emerging concept of biased agonism pharmacology.
Biased agonism pharmacology is based on the discovery that GPCRs can assume multiple conformations that
transduce qualitatively different signals, and ligands can “tune” GPCRs to bias signaling to one pathway or
another. We propose to discern qualitative signaling properties of the M3 mAChR and determine how
canonical (G protein-dependent) versus non-canonical (arrestin-dependent) signaling regulates airway smooth
muscle (ASM) functions that are often dysregulated in COPD. We have discovered both small molecule
orthosteric ligands as well as a peptide that can bias M3 mAChR signaling toward the arrestin signaling
pathway. Preliminary data also strongly suggest arrestin-dependent signaling mediates therapeutically
beneficial ASM functions. Lead agents in hand as well as those that emerge in focused screens will be tested
in cell- and tissue-based studies of ASM signaling and function, and ultimately in an in vivo model of COPD to
discern the utility of these drugs as COPD therapeutics. Three Aims are proposed. Aim 1 will employ genetic
and molecular strategies, including use of mice with arrestin subtype genes ablated, to establish the regulatory
effects of arrestins on M3 mAChR-mediated functions (contraction, growth, and synthetic functions) in airway
smooth muscle. Aim 2 will employ semi-high throughput screening systems, ASM signaling and functional
assays, and novel engineered M3 receptors to fully characterize those biased agents in hand and to discover
additional biased ligands and peptides. Aim 3 will test our lead biased M3 ligands in an in vivo model of COPD
to verify the ability of a biased pharmacology approach to manage the disease. The impact of the proposed
studies lies in their ability to significantly advance the science underlying, and ultimate clinical application of,
biased agonism pharmacology.

## Key facts

- **NIH application ID:** 9859446
- **Project number:** 5R01HL140064-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Tonio Pera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859446

## Citation

> US National Institutes of Health, RePORTER application 9859446, Biased Muscarinic Acetylcholine Receptor Signaling in Obstructive Lung Disease Pathology and Therapy (5R01HL140064-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859446. Licensed CC0.

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