Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: Advantages and limitations

Abstract

Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues.

Structural and Functional Studies of the Modulator NS9283 Reveal Agonist-like Mechanism of Action at α4β2 Nicotinic Acetylcholine Receptors

“…NS9283 improves cognitive function in animal models, and it enhances the analgesic effects of the nonopioid analgesic ABT-594 (14,15). These preclinical data provide hope that positive modulators of ␣4␤2 nAChRs may realize some of the therapeutic benefits (3,8,16) that were anticipated to come from agonist discovery programs (3,17).…”

“…the normal temporal and spatial resolution of neuronal firing is maintained, which may result in better tolerated drugs (7,8). Furthermore, modulator binding sites are often located in less structurally conserved regions than the agonist-binding sites, which suggest that it may be easier to obtain subtypeselective modulators (7)(8)(9).…”

Critical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation

“…The binding sites for PAMs of other Cys-loop receptors, such as GABA A and heteromeric nAChR, have been found at subunit interfaces homologous to, but distinct from, the orthosteric ligand-binding sites (54). These sites are not present in homomeric ␣7 nAChR, because the potential for an orthosteric binding site is present at every subunit interface (6).…”

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

“…For instance, due to their Ca 2+ permeability, it has been speculated that PAMs of a4b2 and a7 nAChRs may have cytotoxic effects as a result of potential Ca 2+ overload upon increased charge transfer. So far, this issue has only been addressed in vitro with a7 nAChRs [102]; however, these results have so far been equivocal. Further studies are therefore needed to explore this potential limitation.…”