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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / agonists
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Alkaloids / chemical synthesis*
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Alkaloids / pharmacology*
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Animals
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Azocines / agonists
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Azocines / chemical synthesis*
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Azocines / pharmacology*
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Binding, Competitive
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Bridged Bicyclo Compounds, Heterocyclic / metabolism
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bungarotoxins / metabolism
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Bungarotoxins / pharmacokinetics
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Calcium / chemistry
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Calcium / metabolism
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Cell Line
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Female
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Gene Expression
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Iodine Radioisotopes
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Molecular Structure
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Neurons / drug effects*
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Neurons / metabolism
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Nicotinic Agonists / chemical synthesis
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Nicotinic Agonists / pharmacokinetics
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Nicotinic Antagonists / chemical synthesis
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Nicotinic Antagonists / pharmacokinetics
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Nitrogen / analysis*
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Oocytes / drug effects
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Pyridines / metabolism
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Pyridines / pharmacokinetics
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Quinolizines / agonists
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Quinolizines / chemical synthesis*
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Quinolizines / pharmacology*
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Radioligand Assay
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Rats
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Receptors, Nicotinic / drug effects*
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Receptors, Nicotinic / genetics
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Receptors, Nicotinic / metabolism
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Structure-Activity Relationship
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Tritium
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Xenopus laevis
Substances
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1,2-bis-N-cytisinylethane
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Alkaloids
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Azocines
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Bridged Bicyclo Compounds, Heterocyclic
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Bungarotoxins
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Iodine Radioisotopes
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N-3-oxobutylcytisine
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N-4-fluorobenzyl cytisine
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Nicotinic Agonists
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Nicotinic Antagonists
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Pyridines
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Quinolizines
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Receptors, Nicotinic
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nicotinic receptor alpha3beta4
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Tritium
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cytisine
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epibatidine
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Nitrogen
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Calcium