Orthosteric and allosteric potentiation of heteromeric neuronal nicotinic acetylcholine receptors

Abstract

This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

“…The clinical lack of efficacy of orthosteric nicotinic agonists might be due to potential cross activity, overdosing, receptor desensitization and/or upregulation [2,14]. Thus, drug development has shifted towards the positive allosteric modulation of α4β2-nAChRs, proposed as an advantageous therapeutic strategy compared to the direct agonist approach [2,15,16]. Since positive allosteric modulators (PAMs) increase the response of the endogenous neurotransmitter acetylcholine (ACh), without activating the receptor per se, the temporal integrity of neurotransmission is preserved, and the risk of overdosing is limited.…”

“…Although several α4β2-PAMs have been characterized, there is only one study thus far that has assessed the potential procognitive efficacy of NS9283 [17], the compound that was further characterized as an unorthodox α4/α4 site-selective agonist [16]. Another α4β2-selective PAM, desformylflustrabromine (dFBr) [18], has been previously shown to suppress nicotine self-administration in rats [19], ameliorates symptoms of nicotine withdrawal in mice [20] and attenuates compulsive-like behaviours in a mouse model of obsessive-compulsive disorder [21].…”

Nicotinic acetylcholine receptors

“…A consequence of subunit diversity for pentameric receptors is the generation of multiple heteromeric receptor subtypes, where differences in a single subunit can have profound or subtle influences on receptor pharmacology and channel function. Wang and Lindstrom () provide an authoritative account of the complex pharmacology arising from distinct stoichiometries of neuronal nAChRs. They compare the contributions of ‘orthodox’ nAChR agonist‐binding sites, at the interface between an α and β subunit, with ‘unorthodox’ sites that occur between two adjacent α subunits.…”

“…In addition to the two classes of orthosteric site, nAChRs present numerous allosteric binding sites that allow either positive or negative modulation of agonist‐evoked responses. Positive allosteric modulators have excited considerable interest as therapeutic candidates and the clinical implications of the considerable pharmacological heterogeneity of nAChRs are briefly reviewed (Wang and Lindstrom, ). Pharmacological complexity is further increased by considering the speed and duration of nAChR desensitization.…”

“…Increasing awareness of the diversity of neuronal nAChRs, composed of subunits arising from a distinct family of genes from those expressed in skeletal muscle (Alexander et al ., ), has stimulated a broader interest in nAChRs, leading to drug discovery programmes for selective nicotinic therapeutic agents aimed at a wide range of neurological and mental health conditions. The subunit diversity and stoichiometry of nAChRs, and the associated pharmacology and clinical implications, are reviewed by Wang and Lindstrom (). Ten years ago, the burgeoning research into nAChRs inspired the first in a series of conferences, ‘nAChRs 2008’, hosted by the Wellcome Trust at Hinxton, Cambridge, UK.…”