Activity of cytisine and its brominated isosteres on recombinant human a7, a4b2 and a4b4 nicotinic acetylcholine receptors

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) a7-, a4b2- and a4b4 nicotinic acetylcholine (nACh) receptors, expressed in Xenopus oocytes and cell lines, have been investigated. Cy and its bromo-isosteres fully inhibited binding of both [a-125I]bungarotoxin ([a-125I]BgTx) to ha7- and [3H]cy to ha4b2- or ha4b4-nACh receptors. 3-Br-cy was the most potent inhibitor of both [a-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 ha7-nACh receptors but behaved as partial agonists at ha4b2- and ha4b4-nACh receptors. 5-Br-cy and 3,5-diBr-cy had low potency and were partial agonists at ha7- and ha4b4-nACh receptors, but they elicited no responses on ha4b2-nACh receptors. Cy and 3-Br-cy produced dual dose±response curves (DRC) at both ha4b2- and ha4b4- nACh receptors, but ACh produced dual DRC only at ha4b2-nACh receptors. Low concentrations of cy, 3-Br-cy and 5-Br-cy enhanced ACh responses of oocytes expressing ha4b2-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 ha4b2-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 af®nities and in functional potencies and efficacies