# Targeting of Alpha7 nAChR for therapeutic effects

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $463,932

## Abstract

The nicotinic acetylcholine receptor (nAChR) a7 subtype has numerous properties that distinguish it from other
nAChRs, including activation by both the neurotransmitter ACh and the ubiquitous tissue factor choline, a
feature that may be associated with its important functional expression in both neuronal and non-neuronal
cells, including cells of the immune system. Expressed in such diverse tissues, a7 nAChR are also recognized
as potentially important therapeutic targets for diverse indications including CNS disorders like Alzheimer's
disease and schizophrenia, as well as peripheral disorders, especially inflammatory diseases and pain.
Traditionally, study of a7 and other nAChRs has focused on ligands that activate or antagonize the receptor's
ion channel; however, it has recently been shown that the best drugs for treating the peripheral disorders
through the cholinergic anti-inflammatory pathway (CAP) may preferentially induce the alternative
conformational states associated with ion channel desensitization. Consistent with the hypothesis that the
selective targeting of a7 receptors for peripheral disorders requires qualitatively different drugs from those for
CNS disorders, cells that mediate a7 control of inflammation do not have a7 receptors with activatible ion
channels, possibly due to the co-expression of other gene products that limit ion channel function and confer
distinct pharmacological profiles for a7 function in those cells. We have used electrophysiological,
biochemical, and molecular biological approaches to determine how the multiple conformational states of a7
are selectively regulated by ligands, and we have used positive allosteric modulators (PAMs) to identify novel
molecules that we characterized as silent agonists. These silent agonists are weak partial agonists in regards
to channel activation but effective activators of CAP. Additionally, our studies of allosteric activators (ago-
PAMs) and mutant receptors that cannot be activated by ACh or other orthosteric agonists has led to the
identification of an allosteric agonist binding site and a new class of ligands that are PAM-dependent channel
activators that also activate CAP. One aim will be to further characterize allosteric activators working with the
structural scaffolds that we have identified, which include both potent small ligands and MrIC conotoxin. The
conotoxin and mutants thereof will provide a template for the design of additional small ligands. We will also
develop new ligands based on a novel sulfonium-based agonist that lacks a charged nitrogen and should have
good brain penetration for indications of neuro-inflammatory pain and disease. We will test our new ligands
and previously identified reference compounds in cell-based assays for the regulation of cytokine production
and mediators of signal transduction that are relevant to inflammatory disease and pain. Data on the reference
compounds will help define a target profile for new compounds. New compoun...

## Key facts

- **NIH application ID:** 10091463
- **Project number:** 5R01GM057481-18
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** ROGER L PAPKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,932
- **Award type:** 5
- **Project period:** 2000-05-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091463

## Citation

> US National Institutes of Health, RePORTER application 10091463, Targeting of Alpha7 nAChR for therapeutic effects (5R01GM057481-18). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10091463. Licensed CC0.

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