title: Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes.
abstract: Cytisine very potently binds and activates the alpha 3 beta 4 and alpha 7 nicotinic subtypes, but only partially agonises the alpha 4 beta 2 subtype. Although with a lower affinity than cytisine, new cytisine derivatives with different substituents on the basic nitrogen (CC1-CC8) bind to both the heteromeric and homomeric subtypes, with higher affinity for brain [3H]epibatidine receptors. The cytisine derivatives were tested on the Ca(2+) flux of native or transfected cell lines expressing the rat alpha 7, or human alpha 3 beta 4 or alpha 4 beta 2 subtypes using Ca(2+) dynamics in conjunction with a fluorescent image plate reader. None elicited any response at doses of up to 30-100 microM, but all inhibited agonist-induced responses. Compounds CC5 and CC7 were also electrophysiologically tested on oocyte-expressed rat alpha 4 beta 2, alpha 3 beta 4 and alpha 7 subtypes. CC5 competitively antagonised the alpha 4 beta 2 and alpha 3 beta 4 subtypes with similar potency, whereas CC7 only partially agonised them with maximum responses of respectively 3% and 11% of those of 1 mM acetylcholine. Neither compound induced any current in the oocyte-expressed alpha 7 subtype, and both weakly inhibited acetylcholine-induced currents. Adding chemical groups of a different class or size to the basic nitrogen of cytisine leads to compounds that lose full agonist activity on the alpha 3 beta 4 and alpha 7 subtypes.
authors.affiliation: CNR, Institute of Neuroscience, Section of Cellular and Molecular Pharmacology, Department of Medical Pharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.
authors.forename: Eric
authors.initials: E
authors.lastname: Carbonnelle
authors.forename: Fabio
authors.initials: F
authors.lastname: Sparatore
authors.forename: Caterina
authors.initials: C
authors.lastname: Canu-Boido
authors.forename: Cristian
authors.initials: C
authors.lastname: Salvagno
authors.forename: Barbara
authors.initials: B
authors.lastname: Baldani-Guerra
authors.forename: Georg
authors.initials: G
authors.lastname: Terstappen
authors.forename: Ruud
authors.initials: R
authors.lastname: Zwart
authors.forename: Henk
authors.initials: H
authors.lastname: Vijverberg
authors.forename: Francesco
authors.initials: F
authors.lastname: Clementi
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gotti
mesh_terms: D000470:Alkaloids / Q000819:agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001392:Azocines / Q000819:agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000493:pharmacokinetics; D002038:Bungarotoxins / Q000378:metabolism / Q000493:pharmacokinetics; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D007457:Iodine Radioisotopes; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics; D009584:Nitrogen / Q000032:analysis*; D009865:Oocytes / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics; D011807:Quinolizines / Q000819:agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium; D014982:Xenopus laevis; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D002118:Calcium; D007457:Iodine Radioisotopes; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D009584:Nitrogen; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D014316:Tritium; C482518:1,2-bis-N-cytisinylethane; C482519:N-3-oxobutylcytisine; C482521:N-4-fluorobenzyl cytisine; D000093843:Quinolizidine Alkaloids; C403530:nicotinic receptor alpha3beta4; C004712:cytisine; C082748:epibatidine