Activity Of Cytisine And Its Brominated Isosteres On Recombinant Human Î±7 Î±4Î²2 And Î±4Î²4 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) Î±7-, Î±4Î²2- and Î±4Î²4 nicotinic acetylcholine (nACh) receptors, expressed in Xenopus oocytes and cell lines, have been investigated. Cy and its bromo-isosteres fully inhibited binding of both [Î±-125l]bungarotoxin ([Î±-125l]BgTx) to hÎ±7- and [3H]cy to hÎ±4Î²2- or hÎ±4Î²4-nACh receptors. 3-Br-cy was the most potent inhibitor of both [Î±-125l]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 hÎ±7-nACh receptors but behaved as partial agonists at hÎ±4Î²2- and hÎ±4Î²4-nACh receptors. 5-Br-cy and 3,5-diBr-cy had low potency and were partial agonists at hÎ±7- and hÎ±4Î²4-nACh receptors, but they elicited no responses on hÎ±4Î²2-nACh receptors. Cy and 3-Br-cy produced dual dose-response curves (DRC) at both hÎ±4Î²2- and hÎ±4Î²4-nACh receptors, but ACh produced dual DRC only at hÎ±4Î²2-nACh receptors. Low concentrations of cy, 3-Br-cy and 5-Br-cy enhanced ACh responses of oocytes expressing hÎ±4Î²2-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 hÎ±4Î²2-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.
Journal of Neurochemistry
Digital Object Identifier (DOI)
Houlihan, Lee M.; Slater, Yvonne; Guerra, Doris L.; Peng, Jian Hong; Kuo, Yen Ping; Lukas, Ronald J.; Cassels, Bruce K.; and Bermudez, Isabel, "Activity Of Cytisine And Its Brominated Isosteres On Recombinant Human Î±7 Î±4Î²2 And Î±4Î²4 Nicotinic Acetylcholine Receptors" (2001). Neurobiology. 184.