Nootropic α7 nicotinic receptor allosteric modulator derived from GABA _A receptor modulators

Abstract

Activation of brain ␣7 nicotinic acetylcholine receptors (␣7 nAChRs) has broad therapeutic potential in CNS diseases related to cognitive dysfunction, including Alzheimer's disease and schizophrenia. In contrast to direct agonist activation, positive allosteric modulation of ␣7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective ␣7 nAChR-positive allosteric modulator (PAM) from a library of GABA A receptor PAMs. Compound 6 (N-(4-chlorophenyl)-␣-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at ␣7 nAChRs, while preserving the rapid native characteristics of desensitization, and has little to no efficacy at other ligand-gated ion channels. In rodent models, it corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement. Compound 6 represents a chemotype for allosteric activation of ␣7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction.cognition ͉ ion channels ͉ memory ͉ nicotine ͉ schizophrenia

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

“…It has been suggested that these receptor subtypes play a role in cognition (Chan et al, 2007;Gray and Roth, 2007;Schreiber et al, 2002). The role of α7 nACh receptors in cognition, is further supported by evidence showing that α7 nACh receptor agonists and positive allosteric modulators improve performance in various tests of working and recognition memory (Pichat et al, 2007;Chan et al, 2007;Timmerman et al, 2007;Ng et al, 2007;Bitner et al, 2007;Redrobe et al, 2009;Hashimoto et al, 2008;Hauser et al, 2009). For a recent review of the involvement of α7 nACh receptors in cognitive processing of relevance to schizophrenia, see Leiser et al 2009. Our laboratory aims to model, in rats, the seven domains of cognition highlighted by the MATRICS initiative as being impaired in schizophrenia patients (Green et al, 2004;Marder and Fenton, 2004).…”

Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

“…Conventional agonists of α7 nAChRs have been extensively studied in preclinical models of neuropsychiatric disorders (8), although few have progressed into clinical studies. Studies of α7-selective PAMs have been reported in animal models (19,44,45) but there is currently no evidence as to the potential therapeutic usefulness of allosteric modulators or allosteric agonists acting on α7 nAChRs. Theoretically, it is possible that a type II PAM might have therapeutic benefits in situations where stronger agonist responses were desirable.…”

Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

“…In addition to this collection of pharmacologically diverse agonists and antagonists, several positive allosteric modulators of nAChRs have been identified (16). Recently, selective positive allosteric modulators of ␣7-type nAChRs have attracted particular attention, arising in part from the suggestion that they may have potential in the treatment of disorders such as Alzheimer's disease and schizophrenia (16)(17)(18)(19). PNU-120596 is a selective potentiator of ␣7 nAChRs, with little or no activity on most other nAChR subtypes (17,20).…”

“…PNU-120596 is a selective potentiator of ␣7 nAChRs, with little or no activity on most other nAChR subtypes (17,20). Recent in vivo studies with this and other ␣7-selective potentiators have provided evidence of effects in cognitive enhancement (18,19) and for efficacy in models of schizophrenia (17). However, despite the considerable interest in these compounds, their mechanism of action is unclear.…”