Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes

Eur J Pharmacol. 2003 Jun 20;471(2):85-96. doi: 10.1016/s0014-2999(03)01817-x.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / agonists
  • Alkaloids / chemical synthesis*
  • Alkaloids / pharmacology*
  • Animals
  • Azocines / agonists
  • Azocines / chemical synthesis*
  • Azocines / pharmacology*
  • Binding, Competitive
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bungarotoxins / metabolism
  • Bungarotoxins / pharmacokinetics
  • Calcium / chemistry
  • Calcium / metabolism
  • Cell Line
  • Female
  • Gene Expression
  • Iodine Radioisotopes
  • Molecular Structure
  • Neurons / drug effects*
  • Neurons / metabolism
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / pharmacokinetics
  • Nicotinic Antagonists / chemical synthesis
  • Nicotinic Antagonists / pharmacokinetics
  • Nitrogen / analysis*
  • Oocytes / drug effects
  • Pyridines / metabolism
  • Pyridines / pharmacokinetics
  • Quinolizines / agonists
  • Quinolizines / chemical synthesis*
  • Quinolizines / pharmacology*
  • Radioligand Assay
  • Rats
  • Receptors, Nicotinic / drug effects*
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism
  • Structure-Activity Relationship
  • Tritium
  • Xenopus laevis

Substances

  • 1,2-bis-N-cytisinylethane
  • Alkaloids
  • Azocines
  • Bridged Bicyclo Compounds, Heterocyclic
  • Bungarotoxins
  • Iodine Radioisotopes
  • N-3-oxobutylcytisine
  • N-4-fluorobenzyl cytisine
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Pyridines
  • Quinolizines
  • Receptors, Nicotinic
  • nicotinic receptor alpha3beta4
  • Tritium
  • cytisine
  • epibatidine
  • Nitrogen
  • Calcium