C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists

J A Abin-Carriquiry, M H Voutilainen, J Barik, B K Cassels, P Iturriaga-Vasquez, I Bermudez, C Durand, F Dajas, S Wonnacott

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Abstract

Neuronal nicotinic acetylcholine receptors subserve predominantly modulatory roles in the brain, making them attractive therapeutic targets. Natural products provide key leads in the quest for nicotinic receptor subtype-selective compounds. Cytisine, found in Leguminosae spp., binds with high affinity to alpha 4 beta 2* nicotinic receptors. We have compared the effect of C3 and C5 halogenation of cytisine and methylcytisine (MCy) on their interaction with native rat nicotinic receptors. 3-Bromocytisine (3-BrCy) and 3-iodocytisine (3-ICy) exhibited increased binding affinity (especially at alpha 7 nicotinic receptors; K-1 similar to 0.1 mu M) and functional potency, whereas C5-halogenation was detrimental. 3-BrCy and 3-ICy were more potent than cytisine at evoking [H-3]dopamine release from striatal slices (EC50 similar to 11 nM), [H-3]noradrenaline release from hippocampal slices (EC50 similar to 250 nM), increases in intracellular Ca2+ in PC12 cells and inward currents in Xenopus oocytes expressing human alpha 3 beta 4 4 nicotinic receptor (EC50 similar to 2 mu M). These compounds were also more efficacious than cytisine. C3-halogenation of cytisine is proposed to stabilize the open conformation of the nicotinic receptor but does not enhance subtype selectivity.
LanguageEnglish
Pages1-11
Number of pages11
JournalEuropean Journal of Pharmacology
Volume536
Issue number1-2
DOIs
StatusPublished - Apr 2006

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Nicotinic Agonists
Halogenation
Nicotinic Receptors
Corpus Striatum
PC12 Cells
Xenopus
Biological Products
Fabaceae
Oocytes
Dopamine
Norepinephrine
cytisine
Brain

Cite this

Abin-Carriquiry, J. A., Voutilainen, M. H., Barik, J., Cassels, B. K., Iturriaga-Vasquez, P., Bermudez, I., ... Wonnacott, S. (2006). C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists. DOI: 10.1016/j.ejphar.2006.02.012

C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists. / Abin-Carriquiry, J A; Voutilainen, M H; Barik, J; Cassels, B K; Iturriaga-Vasquez, P; Bermudez, I; Durand, C; Dajas, F; Wonnacott, S.

In: European Journal of Pharmacology, Vol. 536, No. 1-2, 04.2006, p. 1-11.

Research output: Contribution to journalArticle

Abin-Carriquiry, JA, Voutilainen, MH, Barik, J, Cassels, BK, Iturriaga-Vasquez, P, Bermudez, I, Durand, C, Dajas, F & Wonnacott, S 2006, 'C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists' European Journal of Pharmacology, vol. 536, no. 1-2, pp. 1-11. DOI: 10.1016/j.ejphar.2006.02.012
Abin-Carriquiry JA, Voutilainen MH, Barik J, Cassels BK, Iturriaga-Vasquez P, Bermudez I et al. C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists. European Journal of Pharmacology. 2006 Apr;536(1-2):1-11. Available from, DOI: 10.1016/j.ejphar.2006.02.012
Abin-Carriquiry, J A ; Voutilainen, M H ; Barik, J ; Cassels, B K ; Iturriaga-Vasquez, P ; Bermudez, I ; Durand, C ; Dajas, F ; Wonnacott, S. / C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists. In: European Journal of Pharmacology. 2006 ; Vol. 536, No. 1-2. pp. 1-11
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