Advances in the Discovery of Novel Positive Allosteric Modulators of the α7 Nicotinic Acetylcholine Receptor

Abstract

The alpha7 subtype of the nicotinic acetylcholine receptor (nAChR) is a target of considerable interest in CNS drug discovery, in part due to its implication in diseases of unmet medical need such as schizophrenia and Alzheimer's disease. Pharmacological distinction of this subtype from other nAChRs is exemplified by antagonists such as alpha-bungarotoxin and methyllycaconitine, and more recently by agonists that have emerged from various structural classes. Increasing evidence, both preclinical and clinical, has also demonstrated that alpha7 nAChR agonists and partial agonists can lead to improvements in cognitive performance. An attractive alternative approach to modulating alpha7 nAChR function is to enhance the effects of the endogenous neurotransmitter acetylcholine (ACh) through positive allosteric modulation (PAM). This class of compounds - positive allosteric modulators (PAMs) - could selectively modulate the activity of ACh at alpha7 nAChRs in a manner that may have significant advantages over indiscriminate and direct activation of nAChRs by nicotine/nicotinic agonists or by acetylcholinesterase inhibitors. Validation of the alpha7 nAChR-selective PAM approach requires the identification of potent and selective compounds. Initially identified nAChR allosteric modulators, including 5-hydroxyindole (5-HI), galantamine, bovine serum albumin, and SLURP-1, are weak and nonselective. More recently, potent and alpha7 nAChR-selective PAMs belonging to diverse chemotypes have emerged and are beginning to be optimized as tools for concept validation in preclinical models and in the clinic. This review summarizes the current status of nAChR-selective PAMs, from patents and published literature, and their potential for the treatment of cognitive deficits associated with neuropsychiatric and neurodegenerative disorders and other diseases.

In Vitro Pharmacological Characterization of a Novel Allosteric Modulator of α7 Neuronal Acetylcholine Receptor, 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), Exhibiting Unique Pharmacological Profile

“…Functional nAChR activities were assessed in HEK-293 cells expressing human ␣4␤2 or ␣3␤4 subunits and in IMR-32 cells by measuring intracellular calcium changes using Fluo-4 acetoxymethyl ester or no-wash calcium dye (Applied Biosystems/MDS Analytical Technologies/Molecular Devices, Sunnyvale, CA or Invitrogen, Carlsbad, CA) and the fluorometric imaging plate reader (FLIPR) system (Applied Biosystems/MDS Analytical Technologies/Molecular Devices) as described previously Briggs et al, 2008;Gopalakrishnan et al, 2008;Faghih et al, 2009). The responses in HEK-293 cells expressing ␣7/5-HT 3 chimera were determined using FMP dye (Molecular Devices).…”

“…A-867744 is a representative and optimized compound from a series of pyrrole analogs functioning as positive allosteric modulators of ␣7 nAChRs (Faghih et al, 2009). In initial experiments, the effect of A-867744 was examined as an agonist at human ␣7 nAChRs.…”

“…Both types of ␣7 PAMs have been reported to improve cognitive function or sensory gating deficits (Hurst et al, 2005;Ng et al, 2007;Timmermann et al, 2007). Likewise, in vivo studies with A-867744 in the DBA/2 mouse model showed significant improvement in sensory gating deficits (Faghih et al, 2009). Although molecular and cellular mechanisms responsible for these in vivo observations remain to be elucidated, it is likely that effects on synaptic transmission play a role as shown by the responses of 5-HI and PNU-120596 in rat cerebellum and hippocampus (Frazier et al, 2003;Hurst et al, 2005;Thinschmidt et al, 2008).…”

Methanandamide Allosterically Inhibits in Vivo the Function of Peripheral Nicotinic Acetylcholine Receptors Containing the α7-Subunit

“…The latter may have more favorable properties than ligands at the orthosteric site, e.g. novel positive allosteric modulators of ␣7-nAChRs have been suggested to have significant advantages over indiscriminate and direct activation of nAChRs by nicotine/nicotinic agonists or by acetylcholinesterase inhibitors (Faghih et al, 2007). Likewise, in the case of GABA A receptors, benzodiazepines act therapeutically via allosteric sites, whereas ligands at the orthosteric site of the GABA A receptor play a much less important role.…”

Directed Mutagenesis of Nicotinic Receptors to Investigate Receptor Function

“…The drug galantamine exerts its therapeutic action by allosteric modulation of the nAChRs (Bertrand and Gopalakrishnan, 2007;Maelicke et al, 2001). Understanding the mechanism of allosteric modulation is therefore important for developing novel drugs for treating Alzheimer´s disease (Faghih et al, 2007).…”