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. 2006 May 4;49(9):2673-6.
doi: 10.1021/jm051196m.

Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity

Sheela K Chellappan  1 , Yingxian Xiao, Werner Tueckmantel, Kenneth J Kellar, Alan P Kozikowski
Affiliations

Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity

Sheela K Chellappan et al. J Med Chem. .

Abstract

We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.

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Figures

Figure 1
Figure 1
Figure 2
Figure 2
Figure 3
Figure 3
Scheme 1
Scheme 1
aReagents and conditions: (a) BH3-THF, THF, 0 °C, 5 h, 85%; (b) CH2(OMe)2, BF3·OEt2, CH2Cl2, 0 °C, 3 h, 85%.
Scheme 2
Scheme 2
aReagents and conditions: (a) Pd(PPh3)4, DMF, 130 °C, 15 h, 79%; (b) LiAlH4, THF, -20 °C, 3.5 h, 59%; (c) BnBr, CH3CN, reflux, 2 h; (d) H2 (1 atm), PtO2, Et3N, MeOH, rt, 15 h, cis : trans = 5:1; cis, 67%; (e) MsCl, Et3N, DCM, 0 °C, 30 min, 84%; (f) Toluene, reflux, 3 h, 83%; (g) TFA, rt, 3 h, 91%; (h) H2 (1 atm), 10% Pd-C (1eq w/w), MeOH, rt, 15 h; (i) H2 (1 atm), 20% Pd(OH)2-C (0.1 eq), (Boc)2O, MeOH, reflux, 30 min, 92%; (j) TFA, CH2Cl2, rt, 1 h, 87-93%.
Scheme 3
Scheme 3
aReagents and conditions: (a) PdCl2(PPh3)2, Dioxane, 120 °C, 1 h, 73%; (b) TFA, CH2Cl2, 30 min, 81%. (c) Pd (PPh3)4, K2CO3, DME/H2O, 85 °C, 15 h, 87%; (d) TFA, CH2Cl2, 30 min, 85%.
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