Abstract
Low-nanomolar binding constants were recorded for a series of six 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues with acetylcholine-binding protein (AChBP). The crystal structures of three complexes with AChBP reveal details of molecular recognition in the orthosteric binding site and imply how the other three ligands bind. Comparisons exploiting AChBP as a surrogate for α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) suggest that the key interactions are conserved. The ligands interact with the same residues as the archetypal nAChR agonist nicotine yet display greater affinity, thereby rationalizing their in vivo activity as potent antagonists of nicotine-induced antinociception. An oxyanion-binding site is formed on the periphery of the AChBP orthosteric site by Lys42, Asp94, Glu170 and Glu210. These residues are highly conserved in the human α4, β2 and α7 nAChR sequences. However, specific sequence differences are discussed that could contribute to nAChR subtype selectivity and in addition may represent a point of allosteric modulation. The ability to engage with this peripheral site may explain, in part, the function of a subset of ligands to act as agonists of α7 nAChR.
Highlights
Nicotinic acetylcholine receptors are cationselective pentameric ligand-gated ion channels gated by the neurotransmitters acetylcholine and choline
The pentameric ligand-gated ion channels (pLGICs) family presents a number of therapeutic targets for neurological conditions; Nicotinic acetylcholine receptors (nAChRs) subtypes are key targets for the development of compounds with use in the treatment of nicotine addiction and of pain (Bertrand et al, 2015; Dineley et al, 2015; Bagdas et al, 2018) The discovery of epibatidine [(1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane; Fig. 1], a highly potent but relatively nonselective agonist of nAChR that displays powerful non-opiate-mediated antinociceptive effects, elicited great excitement (Spande et al, 1992; Traynor, 1998)
The affinity of AcAChBP for compounds 1–6 was assessed by Biolayer interferometry (BLI) (Table 2; representative sensorgrams are shown in Supplementary Fig. S2)
Summary
Nicotinic acetylcholine receptors (nAChRs) are cationselective pentameric ligand-gated ion channels (pLGICs) gated by the neurotransmitters acetylcholine and choline. They are the targets of non-endogenous molecules, with the best known being the archetypal agonist nicotine. The pLGIC family presents a number of therapeutic targets for neurological conditions; nAChR subtypes are key targets for the development of compounds with use in the treatment of nicotine addiction and of pain (Bertrand et al, 2015; Dineley et al, 2015; Bagdas et al, 2018) The discovery of epibatidine [(1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane; Fig. 1], a highly potent but relatively nonselective agonist of nAChR that displays powerful non-opiate-mediated antinociceptive effects, elicited great excitement (Spande et al, 1992; Traynor, 1998).
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