Activity of cytisine and its brominated isosteres on recombinant human α7, α4β2 and α4β4 nicotinic acetylcholine receptors

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Abstract
Effects of cytisine (cy), 3-bromocytisine (3-Br-cy), 5-bromocytisine (5-Br-cy) and 3,5-dibromocytisine (3,5-diBr-cy) on human (h) α7-, α4β2- and α4β4 nicotinic acetylcholine (nACh) receptors, expressed in Xenopus oocytes and cell lines, have been investigated. Cy and its bromo-isosteres fully inhibited binding of both [α-125I]bungarotoxin ([α-125I]BgTx) to hα7- and [3H]cy to hα4β2- or hα4β4-nACh receptors. 3-Br-cy was the most potent inhibitor of both [α-125I]BgTx and [3H]cy binding. Cy was less potent than 3-Br-cy, but 5-Br-cy and 3,5-diBr-cy were the least potent inhibitors. Cy and 3-Br-cy were potent full agonists at hα7-nACh receptors but behaved as partial agonists at hα4β2- and hα4β4-nACh receptors. 5-Br-cy and 3,5-diBr-cy had low potency and were partial agonists at hα7- and hα4β4-nACh receptors, but they elicited no responses on hα4β2-nACh receptors. Cy and 3-Br-cy produced dual dose–response curves (DRC) at both hα4β2- and hα4β4-nACh receptors, but ACh produced dual DRC only at hα4β2-nACh receptors. Low concentrations of cy, 3-Br-cy and 5-Br-cy enhanced ACh responses of oocytes expressing hα4β2-nACh receptors, but at high concentrations they inhibited the responses. In contrast, 3,5-diBr-cy only inhibited, in a competitive manner, ACh responses of hα4β2-nACh receptors. It is concluded that bromination of the pyridone ring of cy produces marked changes in effects of cy that are manifest as nACh receptor subtype-specific differences in binding affinities and in functional potencies and efficacies.