Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors

A series of pyridone ring-modified derivatives of (7R,9S)-(−)-cytisine were evaluated for affinity and functional activity at neuromuscular α1β1γδ, ganglionic α3β4, and central neuronal α4β2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the α4β2 subtype.