3-Bromocytisine

Increase in locomotor activity after acute administration of the nicotinic receptor agonist 3-bromocytisine in rats.[Pubmed:20184877]

Eur J Pharmacol. 2010 May 25;634(1-3):89-94.

Nicotinic acetylcholine receptors influence striatal dopaminergic activity and its outcome on motor behavior. For these reasons, nicotinic receptors have been considered as therapeutically relevant targets for Parkinson's disease, in which a dramatic loss of dopamine affects motor functions. The aim of the present work was to compare the effects on locomotor activity induced by the nicotinic agonist cytisine and two brominated derivatives, 5- and 3-Bromocytisine (5-BrCy and 3-BrCy) using nicotine for comparison. After acute systemic administration of the agonists only 3-BrCy induced an increase in locomotor activity. To study the mechanism of action involved in this increase we co-administered 3-BrCy with the nicotinic antagonist mecamylamine and also examined 3-BrCy's effects in rats pre-treated with the long acting nicotinic antagonist chlorisondamine, administered directly in the dorsal and ventral striatum. We studied the role of the dopaminergic system by co-administration of the D2 dopamine receptor antagonist, haloperidol. The results indicate that the increase in motor activity elicited by 3-BrCy was mediated by nicotinic receptors in the dorsal and ventral striatum and depends on the interaction of nicotinic receptors with the dopaminergic system. We conclude that 3-BrCy might be a new tool to study the modulation of the dopaminergic system by nicotinic receptors and their behavioral implications.

alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine.[Pubmed:16720757]

Mol Pharmacol. 2006 Aug;70(2):755-68.

alpha4 and beta2 nicotinic acetylcholine receptor (nAChR) subunits expressed heterologously assemble into receptors with high (HS) and low (LS) sensitivity to acetylcholine (ACh); their relative proportions depend on the alpha4to beta2 ratio. In this study, injection of oocytes with 1:10 alpha4/beta2 subunit cDNA ratios favored expression of HS alpha4beta2 nAChRs, as evidenced by monophasic ACh concentration-response curves, whereas injections with 10:1 cDNA ratios favored expression of LS alpha4beta2 receptors. The stoichiometry was inferred from the shifts in the ACh EC(50) values caused by Leu to Thr mutations at position 9' of the second transmembrane domain of alpha4 and beta2. The 1:10 injection ratio produced the (alpha4)(2)(beta2)(3) stoichiometry, whereas 10:1 injections produced the (alpha4)(3)(beta2)(2) stoichiometry. The agonists epibatidine, 3-[2(S)-azetidinylmethoxy]pyridine (A-85380), 5-ethoxy-metanicotine (TC-2559), cytisine, and 3-Br-cytisine and the antagonists dihydro-beta-erythroidine and d-tubocurarine were more potent at HS receptors. TC-2559 was more efficacious than ACh at HS receptors but was a partial agonist at LS receptors. Epibatidine was more efficacious than ACh at LS receptors and a partial agonist at HS receptors. Cytisine and 5-halogenated cytisines had moderate efficacy at LS receptors but had almost no efficacy at HS receptors. By exploiting the differential effects of ACh, TC-2559 and 5-I-cytisine we evaluated the effects of long-term exposure to nicotine on HS and LS receptors expressed in Xenopus laevis oocytes after cDNA injections or microtransplantation of alpha4beta2 receptors assembled in human embryonic kidney 293 cells. We conclude that nicotine up-regulates HS alpha4beta2 receptors, probably by influencing the assembly of receptors rather than by altering the functional state of LS alpha4beta2 nAChRs.

Activity of cytisine and its brominated isosteres on recombinant human alpha7, alpha4beta2 and alpha4beta4 nicotinic acetylcholine receptors.[Pubmed:11553677]

J Neurochem. 2001 Sep;78(5):1029-43.

Effects of cytisine (cy), 3-Bromocytisine (3-Br-cy), 5-bromocytisine (5-Br-cy) and 3,5-dibromocytisine (3,5-diBr-cy) on human (h) alpha7-, alpha4beta2- and alpha4beta4 nicotinic acetylcholine (nACh) receptors, expressed in Xenopus oocytes and cell lines, have been investigated. Cy and its bromo-isosteres fully inhibited binding of both [alpha-(125)I]bungarotoxin ([alpha-(125)I]BgTx) to halpha7- and [(3)H]cy to halpha4beta2- or halpha4beta4-nACh receptors. 3-Br-cy was the most potent inhibitor of both [alpha-(125)I]BgTx and [(3)H]cy binding. Cy was less potent than 3-Br-cy, but 5-Br-cy and 3,5-diBr-cy were the least potent inhibitors. Cy and 3-Br-cy were potent full agonists at halpha7-nACh receptors but behaved as partial agonists at halpha4beta2- and halpha4beta4-nACh receptors. 5-Br-cy and 3,5-diBr-cy had low potency and were partial agonists at halpha7- and halpha4beta4-nACh receptors, but they elicited no responses on halpha4beta2-nACh receptors. Cy and 3-Br-cy produced dual dose-response curves (DRC) at both halpha4beta2- and halpha4beta4-nACh receptors, but ACh produced dual DRC only at halpha4beta2-nACh receptors. Low concentrations of cy, 3-Br-cy and 5-Br-cy enhanced ACh responses of oocytes expressing halpha4beta2-nACh receptors, but at high concentrations they inhibited the responses. In contrast, 3,5-diBr-cy only inhibited, in a competitive manner, ACh responses of halpha4beta2-nACh receptors. It is concluded that bromination of the pyridone ring of cy produces marked changes in effects of cy that are manifest as nACh receptor subtype-specific differences in binding affinities and in functional potencies and efficacies.

3-Bromocytisine (3-Br-cytisine) is a potent nACh receptors agonist, with IC50s are 0.28, 0.30 and 31.6 nM for hα4β4, hα4β2, and hα7-nACh, respectively. 3-Bromocytisine (3-Br-cytisine) shows different effects on high (HS) and low (LS) ACh sensitivity α4β2 nAChRs with EC50s are 8 and 50 nM, respectively.

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