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 α4β2* 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 α7 nicotinic receptors; Ki∼0.1 μM) and functional potency, whereas C5-halogenation was detrimental. 3-BrCy and 3-ICy were more potent than cytisine at evoking [3H]dopamine release from striatal slices (EC50 ∼11 nM), [3H]noradrenaline release from hippocampal slices (EC50 ∼250 nM), increases in intracellular Ca2+ in PC12 cells and inward currents in Xenopus oocytes expressing human α3β4 nicotinic receptor (EC50 ∼2 μM). 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. © 2006 Elsevier B.V. All rights reserved.
CITATION STYLE
Abin-Carriquiry, J. A., Voutilainen, M. H., Barik, J., Cassels, B. K., Iturriaga-Vásquez, P., Bermudez, I., … Wonnacott, S. (2006). C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists. European Journal of Pharmacology, 536(1–2), 1–11. https://doi.org/10.1016/j.ejphar.2006.02.012
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