Recent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors

Abstract

Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.

Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure–activity relationships studies

“…Collectively, cumulative testimonies gained both from preclinical and clinical examinations confirmed that the cholinergic system acts a deciding character in cognitive function (Yu et al, 2014;Sarter and Kim, 2015). Further, concrete loss of the nAChRs is perceived in degenerative neurological disorders such as Alzheimer's disease with specific relation of the a7 nAChR subtype (Taly et al, 2009;Chiang and Koo, 2014).…”

Neuronal effects of nicotine during auditory selective attention

“…Indeed, the cognitive-enhancing effects of nicotinic receptor targeting compounds are currently being investigated in Alzheimer's disease (Valles et al 2014), autism (Ghaleiha et al 2013), attention deficit (hyperactivity) disorder (Childress and Sallee 2014; Fleisher and McGough 2014), depression (Yu et al 2014), schizophrenia (Freedman 2014), and healthy individuals (Demeter and Sarter 2013). …”

The possible role of maternal bonding style and CHRNB2 gene polymorphisms in nicotine dependence and related depressive phenotype

“…Other studies, however, did not find evidence for these neuropsychiatric side effects (Cinciripini et al, 2013;Garza et al, 2011;Thomas et al, 2013). Nevertheless, a recent study suggests that varenicline may have a protective effect on depressed mood (Cinciripini et al, 2013); furthermore, α4β2 nAChR as potential antidepressant targets have been implicated (Yu et al, 2014). Therefore, a significant genetic association with suicidal phenotype among smokers is highly relevant and can provide an important basis for further pharmacogenetic studies of the CHRNB2 gene because vulnerability to suicidal behavior can be a key to choosing safer cessation therapy.…”