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Review
. 2023 Jan 28;28(3):1270.
doi: 10.3390/molecules28031270.

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

Dina Manetti  1 , Silvia Dei  1 , Hugo R Arias  2 , Laura Braconi  1 , Alessio Gabellini  1 , Elisabetta Teodori  1 , Maria Novella Romanelli  1
Affiliations
Review

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

Dina Manetti et al. Molecules. .

Abstract

Positive allosteric modulators (PAMs), negative allosteric modulators (NAMs), silent agonists, allosteric activating PAMs and neutral or silent allosteric modulators are compounds capable of modulating the nicotinic receptor by interacting at allosteric modulatory sites distinct from the orthosteric sites. This survey is focused on the compounds that have been shown or have been designed to interact with nicotinic receptors as allosteric modulators of different subtypes, mainly α7 and α4β2. Minimal chemical changes can cause a different pharmacological profile, which can then lead to the design of selective modulators. Experimental evidence supports the use of allosteric modulators as therapeutic tools for neurological and non-neurological conditions.

Keywords: desensitization; negative allosteric modulator; nicotinic acetylcholine receptor; positive allosteric modulator; α4β2; α7.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Examples of type I, type II and type I/type II intermediate α7-positive allosteric modulators (PAMs).
Figure 2
Figure 2
Examples of allosteric activating PAMs (Ago-PAM) and silent agonist.
Figure 3
Figure 3
Structure of the first type I PAM discovered.
Figure 4
Figure 4
Allosteric modulators with an ureidic function.
Figure 5
Figure 5
Cryo-EM structure of the human α7 nAChR (pdb:7EKT) showing the intersubunit site for PNU-120596 (yellow), the archetype of type II PAMs, located in the TMD (modified from reference [58]). The ECD binding site for NS-1738 (magenta), a typical type I PAM, was obtained by molecular docking as previously described [31]. Only one of five sites per each PAM is shown for simplicity.
Figure 6
Figure 6
Examples of non-selective αAChR PAMs.
Figure 7
Figure 7
Examples of type I and type II α7-PAMs with a cyclopropane ring.
Figure 8
Figure 8
Examples of PAMs with an amide function.
Figure 9
Figure 9
Examples of type II α7-PAMs with arylsulfonamide ring.
Figure 10
Figure 10
Allosteric modulators with different pharmacological profile based on stereochemistry.
Figure 11
Figure 11
Arylsulfonamide allosteric modulators.
Figure 12
Figure 12
α7-PAMs from natural sources.
Figure 13
Figure 13
Nicotinic agents in clinical trials by U.S. National Institutes of Health.
Figure 14
Figure 14
Allosteric modulators of the α4β2 nAChR.
Figure 15
Figure 15
Allosteric modulator of α6β2*, α3β2, and α9α10 nAChR subtypes.
Figure 16
Figure 16
Negative allosteric modulators (NAMs) of different nAChR subtypes.
See this image and copyright information in PMC

References

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