Novel quinuclidine derivatives to investigate the alpha-7 nicotinic acetylcholine receptor activation: new insight and perspectives

The homopentameric α7 nicotinic acetylcholine receptor (nAChR) belongs to the large cys-loop superfamily of neurotransmitter-gated ion channels and is widely expressed in neuronal cells, central and autonomic nervous system, and non-neuronal cells including immune cells, adipocytes, lung endothelial and epithelial cells. Given their widespread distribution and peculiar features, such as rapid channel activation and inactivation kinetics and high calcium permeability, the α7 nAChRs have been extensively investigated and appear to be implicated in central and peripheral diseases/pathological conditions, e.g. cognition disorders, schizophrenia, pain and inflammation. Growing findings suggest the involvement of α7 nAChRs in processes beyond their channel activity.1 Indeed, it has been proposed that they may mediate both channel activation-dependent and -independent forms of signaling.2,3 Recently, a direct coupling of the α7 nAChR to G proteins was hypothesized whereby its activation should be closely associated to the G protein intracellular signaling cycle, with the signal transduction being mediated through sites located in the well conserved α7 intracellular domain.4 The observation that some efficacious α7 anti-inflammatory modulators act as silent agonists, i.e. ligands which are unable to produce channel activation but can induce desensitized conformations of the receptor, seems to support these hypotheses.5 With the aim of further investigating the mechanisms of activation of the α7 nAChR, we designed, synthesized and tested novel spiro-Δ2-isoxazoline and methylene-1,2,4-oxadiazole derivatives connected to the quinuclidine ring, a structural moiety found in various α7 nAChR ligands (Figure 1). Figure 1. Structures of the newly synthesized quinuclidine-containing nicotinic ligands. The new derivatives were assayed in human α7 nAChRs expressed in Xenopus laevis oocytes by means of the two-electrode voltage clamping technique, applying a protocol developed by Papke et al.6 Interestingly, the biological data put in evidence a scaffold for the development of effective α7 nAChR silent agonists. Thus, our work could pave the way to a new class of α7 receptor activators endowed with a promising therapeutic potential.