Regio- and diastereoselective functionalization of (−)-cytisine

Houllier, Nicolas; Gouault, Sonia; Lasne, Marie‐Claire; Rouden, Jacques

doi:10.1016/j.tet.2006.09.057

Cited by 20 publications

(8 citation statements)

References 34 publications

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“…have not yet entered the clinic (Chellappan, Xiao, Tueckmantel, Kellar, & Kozikowski, 2006;Houllier, Gouault, Lasne, & Rouden, 2006;Imming, Klaperski, Stubbs, Seitz, & Gundisch, 2001;Kozikowski, et al, 2007;Marcaurelle, Johannes, Yohannes, Tillotson, & Mann, 2009;Philipova, et al, 2015;Rouden, et al, 2002). Varenicline (Chantix®) has four rings, two more than nicotine or cytisine, and is currently the only FDA-approved smoking-cessation drug, but the modest quit rate of ~18% at 12 months invites further investigation (Coe, et al, 2005;Mills, Wu, Spurden, Ebbert, & Wilson, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Prior work suggests that partial agonists with lower efficacy than nicotine could serve as effective smoking-cessation drugs ( Rose et al, 1994 ), and efforts continue in that direction ( Rollema and Hurst, 2018 ). Another plant alkaloid, (-)-cytisine (also called cytisinicline and Tabex), an α4β2 nAChR partial agonist, served as a basis for the synthesis of analogs that have not yet entered the clinic ( Chellappan et al, 2006 ; Houllier et al, 2006 ; Imming et al, 2001 ; Kozikowski et al, 2007 ; Marcaurelle et al, 2009 ; Philipova et al, 2015 ; Rouden et al, 2002 ). Varenicline (Chantix) has four rings, two more than nicotine or cytisine, and is currently the only FDA-approved smoking-cessation drug, but the modest quit rate of ~18% at 12 months invites further investigation ( Coe et al, 2005 ; Mills et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands

Nichols

Blumenfeld

Fan

et al. 2022

eLife

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Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug sensing fluorescent reporters ('iDrugSnFRs') for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by > 30 fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands

Nichols

Blumenfeld

Fan

et al. 2022

eLife

View full text Add to dashboard Cite

show abstract

“…Prior work suggests that partial agonists with lower efficacy than nicotine could serve as effective smoking-cessation drugs (Rose, et al, 1994), and efforts continue in that direction (Rollema & Hurst, 2018). Another plant alkaloid, (-)-cytisine (also called cytisinicline and Tabex®), an α4β2 nAChR partial agonist, served as a basis for the synthesis of analogs which have not yet entered the clinic (Chellappan, Xiao, Tueckmantel, Kellar, & Kozikowski, 2006;Houllier, Gouault, Lasne, & Rouden, 2006;Imming, Klaperski, Stubbs, Seitz, & Gundisch, 2001;Kozikowski, et al, 2007;Marcaurelle, Johannes, Yohannes, Tillotson, & Mann, 2009;Philipova, et al, 2015;Rouden, et al, 2002). Varenicline (Chantix®) has four rings, two more than nicotine or cytisine, and is currently the only FDA-approved smoking-cessation drug, but the modest quit rate of ~18% at 12 months invites further investigation (Coe, et al, 2005;Mills, Wu, Spurden, Ebbert, & Wilson, 2009).…”

Section: Introductionmentioning

confidence: 99%

Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands

Nichols

Blumenfeld

Fan

et al. 2021

Preprint

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Nicotinic partial agonists provide a partial aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives – 10-fluorocytisine and 9-bromo-10-ethylcytisine. Development of the series was aided and explained by the first atomic-scale structural studies on liganded periplasmic binding protein-based biosensors. Members of the series detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and primary mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by > 30 fold. The new nicotinic iDrugSnFRs, in combination with previously described nicotine and varenicline sensors, provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

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“…This has been successfully applied to the synthesis of cytisine (1, Scheme 2) as well as cytisine analogues and other lupin alkaloids. 12 Scheme 2 Lactam enolate approach to cytisine (1) 12 Application of this enolate-addition strategy to kuraramine is outlined in Scheme 3, and we targeted an This chemistry is interesting in terms of its relationship to the transformations shown in Scheme 1 and the earlier work of Rouden 7,8a and others 14 involving (presumably) carbonyl-directed metalation of an N-alkyl pyridone. This directing effect is powerful but the cyclization pathway outlined within structure 8 also involves formation of a seven-membered ring, which represents a larger ring than we had previously achieved with this cyclization protocol.…”

Section: Scheme 1 Synthesis (+)-Kuraramine (3) From (-)-N-methylcytisine (2)mentioning

confidence: 99%

Synthesis of (+)-Kuraramine

Frigerio¹,

Haseler²,

Gallagher³

2010

Synlett

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Regio- and diastereoselective functionalization of (−)-cytisine

Cited by 20 publications

References 34 publications

Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands

Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands

Fluorescence Activation Mechanism and Imaging of Drug Permeation with New Sensors for Smoking-Cessation Ligands

Synthesis of (+)-Kuraramine

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