C3-halogenation of cytisine generates potent and efficacious nicotinic receptor agonists.
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 alpha4beta2* 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 alpha7 nicotinic receptors; Ki approximately 0.1 microM) 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 approximately 11 nM), [3H]noradrenaline release from hippocampal slices (EC50 approximately 250 nM), increases in intracellular Ca2+ in PC12 cells and inward currents in Xenopus oocytes expressing human alpha3beta4 nicotinic receptor (EC50 approximately 2 microM). 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.
IIBCE, Montevideo, Uruguay.
J Andrés
JA
Abin-Carriquiry
Merja H
MH
Voutilainen
Jacques
J
Barik
Bruce K
BK
Cassels
Patricio
P
Iturriaga-Vásquez
Isabel
I
Bermudez
Claudia
C
Durand
Federico
F
Dajas
Susan
S
Wonnacott
D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001392:Azocines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D011807:Quinolizines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014981:Xenopus; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D002118:Calcium; D004298:Dopamine; D006842:Hydrocarbons, Brominated; D009538:Nicotine; D018722:Nicotinic Agonists; D009638:Norepinephrine; D011807:Quinolizines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C004712:cytisine; D000093843:Quinolizidine Alkaloids