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Review
. 2025 Jul;45(4):1251-1274.
doi: 10.1002/med.22108. Epub 2025 Mar 23.

Light-Activated Pharmacological Tools for Exploring the Cholinergic System

Alessio Colleoni  1   2 , Giulia Galli  1 , Clelia Dallanoce  1 , Marco De Amici  1 , Pau Gorostiza  3   4   5 , Carlo Matera  1
Affiliations
Review

Light-Activated Pharmacological Tools for Exploring the Cholinergic System

Alessio Colleoni et al. Med Res Rev. 2025 Jul.

Abstract

Cholinergic transmission plays a critical role in both the central and peripheral nervous systems, affecting processes such as learning, memory, and inflammation. Conventional cholinergic drugs generally suffer from poor selectivity and temporal precision, leading to undesired effects and limited therapeutic efficacy. Photopharmacology aims to overcome the limitations of traditional drugs using photocleavable or photoswitchable ligands and spatiotemporal patterns of illumination. Spanning from muscarinic and nicotinic modulators to cholinesterase inhibitors, this review explores the development and application of light-activated compounds as tools for unraveling the role of cholinergic signaling in both physiological and pathological contexts, while also paving the way for innovative phototherapeutic approaches.

Keywords: muscarinic acetylcholine receptors; nicotinic acetylcholine receptors; photopharmacology; photoswitch; uncaging.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Representative sketch of cholinergic signaling under physiological conditions versus light‐based modulation. Comparison of natural cholinergic transmission (left) and light‐controlled modulation (right) at nicotinic (a) and muscarinic (b) acetylcholine receptors, as well as acetylcholinesterase (c), highlighting their functional effects. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
(a) First photocleavable cholinergic modulators reported in the literature. (b) Photolytic reaction of “cage I” (2) to release carbamoylcholine iodide. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Photocleavable nicotine‐based (6 and 7) and ABT594‐based (8) caged agonists of nAChRs. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
First discovered photoswitchable modulators of AChRs. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 5
Figure 5
Photoswitchable modulators of nAChRs developed by Trauner's and Kramer's groups. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 6
Figure 6
Most recently developed photoswitchable modulators of nAChRs. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 7
Figure 7
Photolytic reaction of 17 to release acetylcholine. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 8
Figure 8
Iperoxo‐based photoswitchable modulators of mAChRs. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 9
Figure 9
Most recently developed photoswitchable modulators of mAChRs. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 10
Figure 10
Photocleavable cholinesterase (AChE) modulators. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 11
Figure 11
Photoswitchable cholinesterase modulators. [Color figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

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