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 affinity α7 nAChR.

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

“…In this regard, galantamine, a cholinesterase inhibitor that is also a α7 nAChR-PAM has shown neurocognitive improvement in subjects with schizophrenia (Buchanan et al, 2008; Schubert et al, 2006). A number of type I and type II PAMs have shown beneficial effects on sensory gating, working memory and executive functions in animal models (reviewed in (Beinat et al, 2015; Terry Jr et al, 2015). However, a recent phase I clinical trial with JNJ-39393406, an α7 nAChR PAM, did not reveal any beneficial effects on P50 sensory gating and other electrophysiological markers of early information processing in regularly smoking patients with schizophrenia (Winterer et al, 2013).…”

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review

“…This receptor activity may be inhibited by noncompetitive and allosteric mechanisms, in which the ligand does not compete with agonists and binds to a site other than the orthosteric (active) site. On the other hand, a competitive mechanism is when there is competition between agonists for the active site to activate receptors . Furthermore, we stress that binding sites may be situated on the extracellular, transmembrane, or intracellular domains of nAChR …”

“…This latter case, which could be translated to the inhibition/activation of α7 nAChR mediated by Aβ is a controversial topic that has been reviewed elsewhere . Nevertheless, is important to note that this receptor is directly related to most of the significant pathophysiological patterns observed in AD …”

Specific Agonists and Antagonists of Serotonergic Receptors in theTreatment of Cognitive Symptoms in Alzheimer's Disease

“…An allosteric modulator of the M1 muscarinic cholinergic receptor might improve cognitive symptoms in Alzheimer patients [6]. Not only agonism at muscarinic cholinergic receptors, but also agonism at alpha4beta2 nicotinic and alpha7 nicotinic cholinergic receptors can improve cognitive symptoms in Alzheimer's disease [7].…”