Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Abstract

The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer's disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of "multitarget-directed ligands" (MTDLs), the development and/or identification of compounds that exhibit "multifunctional" activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), "repurposing" strategies for existing compounds that have other clinical indications, and novel "adjunctive" treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, "multifunctional" properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity α4β2 nAChR and the low affinity α7 nAChR.

Keywords: Alzheimer; Cholinergic; Memory; Mild Cognitive Impairment; Schizophrenia; ’s disease.

Fig. 1

Diagram illustrating potential “multifunctional” activities (e.g., pro-cognitive, antipsychotic-like, and neuroprotective effects) of ligands of the heteromeric, high affinity α4β2 nAChR and the homomeric, low affinity α7 nAChR. These subtypes are the two most abundant nAChRs found in the mammalian brain. Both receptors consist of five subunits arranged around a central channel that opens when endogenous ligands such as acetylcholine (ACh) or exogenous ligands (nicotine) bind at the orthosteric site allowing cations to flow through the channel into the neuron causing depolarization. Allosteric sites are the target of positive allosteric modulators (PAMs) and they are located at a site which is distinct from the orthosteric where they serve to indirectly influence (modulate) the effects of the agonist. The α7 nAChR is composed of five α7 subunits and the α4β2 nAChR is composed of two α4 subunits and three β2 subunits. The α4β2 nAChR allows passage of both calcium (Ca⁺⁺) and sodium (Na⁺) ions, whereas the α7 nAChR principally allows passage of calcium ions. In neurons, most α4β2 and α7 nAChRs are found at presynaptic sites, however they can be also found at both postsynaptic, perisynaptic and somatodendritic sites. Moreover, both subtypes can be found on cholinergic, dopaminergic, noradrenergic, GABAergic, glutamatergic, and other neuronal phenotypes [191,192,193,194].