title: Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 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) alpha7-, alpha4beta2- and alpha4beta4 nicotinic acetylcholine (nACh) receptors, expressed in Xenopus oocytes and cell lines, have been investigated. Cy and its bromo-isosteres fully inhibited binding of both [alpha-(125)I]bungarotoxin ([alpha-(125)I]BgTx) to halpha7- and [(3)H]cy to halpha4beta2- or halpha4beta4-nACh receptors. 3-Br-cy was the most potent inhibitor of both [alpha-(125)I]BgTx and [(3)H]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 halpha7-nACh receptors but behaved as partial agonists at halpha4beta2- and halpha4beta4-nACh receptors. 5-Br-cy and 3,5-diBr-cy had low potency and were partial agonists at halpha7- and halpha4beta4-nACh receptors, but they elicited no responses on halpha4beta2-nACh receptors. Cy and 3-Br-cy produced dual dose-response curves (DRC) at both halpha4beta2- and halpha4beta4-nACh receptors, but ACh produced dual DRC only at halpha4beta2-nACh receptors. Low concentrations of cy, 3-Br-cy and 5-Br-cy enhanced ACh responses of oocytes expressing halpha4beta2-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 halpha4beta2-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.
authors.affiliation: School of Biological and Molecular Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Houlihan
authors.forename: Y
authors.initials: Y
authors.lastname: Slater
authors.forename: D L
authors.initials: DL
authors.lastname: Guerra
authors.forename: J H
authors.initials: JH
authors.lastname: Peng
authors.forename: Y P
authors.initials: YP
authors.lastname: Kuo
authors.forename: R J
authors.initials: RJ
authors.lastname: Lukas
authors.forename: B K
authors.initials: BK
authors.lastname: Cassels
authors.forename: I
authors.initials: I
authors.lastname: Bermudez
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004594:Electrophysiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007457:Iodine Radioisotopes; D009865:Oocytes / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014316:Tritium; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002038:Bungarotoxins; C579167:Chrna7 protein, human; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C427403:alpha(4)beta(4) nicotinic receptor; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D014316:Tritium; C103182:5-bromocytosine; D003596:Cytosine; D000109:Acetylcholine