Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes.
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.
Carbonnelle
Eric
E
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.
Sparatore
Fabio
F
Canu-Boido
Caterina
C
Salvagno
Cristian
C
Baldani-Guerra
Barbara
B
Terstappen
Georg
G
Zwart
Ruud
R
Vijverberg
Henk
H
Clementi
Francesco
F
Gotti
Cecilia
C
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
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