# Molecular Regulation of Cardiovascular 7 TM Receptors

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $705,383

## Abstract

PROJECT SUMMARY/ABSTRACT
MOLECULAR REGULATION OF CARDIOVASCULAR SEVEN TRANSMEMBRANE
RECEPTORS. All aspects of cardiovascular function are regulated by members of the seven
transmembrane receptor (7TMR or GPCR) family, and they are the commonest target of
therapeutic drugs. A universal mechanism regulating these receptors is desensitization of
heterotrimeric G protein signaling. Classically, this is mediated by a two-step process in which
activated receptors are phosphorylated by G protein-coupled receptor kinases, leading to the
binding of a β-arrestin (βarr) molecule which sterically interdicts further activation of the G protein.
More recently it has become clear that βarrs can also serve as multifunctional adaptors which act
as signal transducers in their own right. Moreover, for many receptors, ligands can be found which
disproportionately activate either G protein- or βarr-mediated signaling—i.e., "biased ligands"
which may possess greater specificity of action and fewer side effects. Biased drugs for GPCR's
represent a major, as yet largely unmined opportunity for drug development. Another such
untapped opportunity to develop drugs with greater specificity and safety is presented by allosteric
ligands which, rather than binding to the orthosteric site of the receptors, where endogenous
ligands bind, interact with other sites. Accordingly, this proposal has three closely linked aims
which involve laying the groundwork for targeting both of these largely untapped opportunities by
developing the first biased allosteric ligands for a receptor of great cardiovascular significance,
the angiotensin II type I receptor (AT1R) as well as for the βarrs. In the process we aim to also
develop a molecular and atomic level understanding of how biased allosteric GPCR drugs
regulate signaling. These aims are: 1. To discover the first small molecule biased allosteric
modulators of the AT1R; 2. To discover novel small molecule allosteric modulators of the signal
transducer βarr; 3. To elucidate the mechanisms of allosteric regulation of downstream effectors
of βarrs. The insights which we will generate have the potential to guide the design of powerful
new cardiovascular drugs and will further our understanding of the conserved signaling
mechanisms of the greater GPCR family.

## Key facts

- **NIH application ID:** 10892258
- **Project number:** 5R01HL016037-52
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** ROBERT J LEFKOWITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $705,383
- **Award type:** 5
- **Project period:** 1976-09-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892258

## Citation

> US National Institutes of Health, RePORTER application 10892258, Molecular Regulation of Cardiovascular 7 TM Receptors (5R01HL016037-52). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10892258. Licensed CC0.

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