α7 Nicotinic receptor modulators for cognitive deficits in schizophrenia and Alzheimer's disease

Nicotinic receptors (nAChR), a class of ligand-gated ion channels, are attractive targets in a variety of CNS diseases. The low-affinity α7 nAChR modulate the levels of various neurotransmitters, their receptor density is affected in schizophrenia and a single nucleotide polymorphism in the promoter region has been associated with higher risk for schizophrenia.

This article reviews the scientific rationale for α7 nAChR stimulation and presents a selection of α7-positive modulators that are in development for cognitive deficits, both in Alzheimer's disease and in cognitive impairment associated with schizophrenia. The available clinical information is reviewed and the translational difficulties are discussed.

In contrast to preclinical models, clinical proof-of-concept studies so far have not shown clear unequivocal cognitive benefit, although there are signs of clinical efficacy on specific cognitive scales and on negative symptoms. Possible problems associated with the clinical development include the impact of dosage and dosing schedule on the balance between activation and desensitization of the ion channel, the selection of comedication, robust human target engagement data and the choice of clinical readout scales. A better understanding of the human biology of α7 nAChR is essential for improving the successful clinical development of this promising target.