Activity of cytisine and its brominated isosteres on recombinant human alpha 7, alpha 4 beta 2 and alpha 4 beta 4 nicotinic acetylcholine receptors

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) alpha7-, alpha4 beta 2- and alpha4 beta4 nicotinic acetylcholine (nACh) receptors, expressed in Xenopus oocytes and cell lines, have been investigated. Cy and its bromo-is osteres fully inhibited binding of both [alpha-I-125]bungarotoxin ([alpha-I -125]BgTx) to h alpha7- and [H-3]cy to h alpha4 beta2- or h alpha4 beta4-nA Ch receptors. 3-Br-cy was the most potent inhibitor of both [alpha-I-125]Bg Tx and [H-3]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 h alpha7-nACh receptors but behaved as partial agonists at h a lpha4 beta2- and h alpha4 beta4-nACh receptors. 5-Br-cy and 3,5-diBr-cy had low potency and were partial agonists at h alpha7-and h alpha4 beta4-nACh receptors, but they elicited no responses on h alpha4 beta2-nACh receptors. Cy and 3-Br-cy produced dual dose-response curves (DRC) at both h alpha4 b eta2- and h alpha4 beta4-nACh receptors, but ACh produced dual DRC only at h alpha4 beta2-nACh receptors. Low concentrations of cy, 3-Br-cy and 5-Br-c y enhanced ACh responses of oocytes expressing h alpha4 beta2-nACh receptor s, but at high concentrations they inhibited the responses. In contrast, 3, 5-diBr-cy only inhibited, in a competitive manner, ACh responses of h alpha 4 beta2-nACh receptors. It is concluded that bromination of the pyridone ri ng of cy produces marked changes in effects of cy that are manifest as nACh receptor subtype-specific differences in binding affinities and in functio nal potencies and efficacies.