Nicotinic pharmacology of anatoxin analogs. II. Side chain structure-activity relationships at neuronal nicotinic ligand binding sites.

Eighteen analogs of (+)-anatoxin-a were evaluated for nicotinic potency at two putative nicotinic acetylcholine receptor sites in the central nervous system. The affinities of the analogs for [3H]nicotine and [125I]alpha-bungarotoxin binding sites were compared. This series of analogs, with modifications to the side chain moieties of the parent structure, enables the importance (for nicotinic binding) of hydrogen bonding strength, planarity, size and steric configuration of this region of the molecule to be assessed. These studies confirm the importance of the side chain stereochemistry and the subordinate role of H-bonding strength of anatoxin analogs. Of all the analogs tested, the parent compound (+)-anatoxin-a is the most potent competitor of ligand binding. Although all analogs have higher affinity at the 3H-nicotine site compared to the alpha-[125I]bungarotoxin site, the rank order of potency is generally the same at both central nervous system sites, and agrees with the order at the muscle nicotinic receptor. However, the simple methoxyamide and the isoxazolidide analogs appear more selective for the neuronal nicotinic receptor subtype identified by 3H-nicotine, indicative of structural differences among the agonist recognition sites.