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Alkyl‐modified side chain variants of anatoxin‐a: A series of potent nicotinic agonists
Author(s) -
Thomas Philip,
Brough Paul A.,
Gallagher Timothy,
Wonnacott Susan
Publication year - 1994
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430310210
Subject(s) - nicotinic agonist , chemistry , stereochemistry , acetylcholine receptor , moiety , pharmacophore , nicotine , agonist , nicotinic acetylcholine receptor , receptor , structure–activity relationship , alkyl , biochemistry , organic chemistry , in vitro , biology , neuroscience
The potent nicotinic agonist anatoxin‐a has a semi‐rigid structure amenable to chemical synthesis and modification, making it an attractive candidate for exploring the structure‐activity relationships of ligands at nicotinic acetylcholine receptors. Racemic anatoxin‐a and a series of three analogues with one or more methine or methylene units added to the acetyl sidechain were synthesised and designated homoanatoxin, propylanatoxin, and isopropylanatoxin. In competition binding assays on two neuronal nicotinic receptors in rat brain membranes, labelled with [ 3 H]nicotine and [ 125 I]αbungarotoxin, the analogues retained or exceeded the potency of the parent structure. K i values for anatoxin‐a, homoanatoxin, propylanatoxin, and isopropylanatoxin were 19, 5.5, 24 and 7.5 nM, respectively, at the [ 3 H]nicotine site and 900, 340, 40, and 120 nM, respectively, at the [ 125 I]αbungarotoxin site. Thus propylanatoxin appears to show a preference for the latter receptor site. Functional potencies of homoanatoxin and isopropylanatoxin were determined at neuronal α7 nicotinic receptors reconstituted in Xenopus oocytes, by two electrode voltage clamp recording. EC 50 values of 0.72 μM and 0.66 μM were determined, similar to that previously published for (+)anatoxin‐a. Molecular modelling of anatoxin‐a and its alkyl‐modified analogues shows them to have very similar energy profiles, consistent with their similar potencies. In the preferred (low energy) conformation, the enone moiety adopts an s‐trans arrangement, although this configuration does not fit the classical pharmacophore model for nicotinic ligands. This series of alkyl‐modified analogues based on anatoxin‐a provides some novel potent nicotinic agonists and with propylanatoxin, receptor subtype selectivity may be emerging. This rational approach to ligand design also enables us to explore further the requirements for ligand recognition through the application of computational chemistry. © 1994 Wiley‐Liss, Inc.