Chemical Medicine: Novel 10‐Substituted Cytisine Derivatives with Increased Selectivity for α4β2 Nicotinic Acetylcholine Receptors

Kozikowski, Alan P.; Chellappan, Sheela K.; Xiao, Yingxian; Bajjuri, Krishna; Yuan, Hongbin; Kellar, Kenneth J.; Petukhov, Pavel A.

doi:10.1002/cmdc.200700073

Cited by 26 publications

(27 citation statements)

References 58 publications

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“…Ring-substituted cytisine derivatives have been generated previously to further investigate affinity and/or selectivity variations in binding to the α4β2 receptor subtype (36, 37). These cytisine derivatives mainly target the pyridone ring (21, 38, 39) or the piperidine ring nitrogen (21, 38, 40).…”

Section: Resultsmentioning

confidence: 99%

Structural Characterization of Binding Mode of Smoking Cessation Drugs to Nicotinic Acetylcholine Receptors through Study of Ligand Complexes with Acetylcholine-binding Protein

Rucktooa

Haseler

Elk

et al. 2012

Journal of Biological Chemistry

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Background: Cytisine and varenicline are smoking cessation drugs binding to nicotinic receptors (nAChRs).Results: We studied crystal structures of cytisine and varenicline with AChBP and analyzed binding of α4β2-like or α7-like AChBP mutants to cytisine.Conclusion: Ligand selectivity relies on residues beyond the binding site primary shell.Significance: These structures will contribute to designing novel compounds targeting specific nAChR subtypes.

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Section: Resultsmentioning

confidence: 99%

Structural Characterization of Binding Mode of Smoking Cessation Drugs to Nicotinic Acetylcholine Receptors through Study of Ligand Complexes with Acetylcholine-binding Protein

Rucktooa

Haseler

Elk

et al. 2012

Journal of Biological Chemistry

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“…In terms of analogues, manipulation of cytisine itself is readily achievable at C3 and C5, C10, and N12 [11][12][13][14][15][16][17][18][19][20] but interest in cytisine as a target for total synthesis has also been significant as well as the synthesis of cytisine derivatives [21,22].…”

Section: Introductionmentioning

confidence: 99%

The Role of Halogen Bonding in Crystal Structures of 3-Halogeno Cytisine Derivatives

Przybył

Kubicki

2012

J Chem Crystallogr

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The crystal structures of three 3-halogeno derivatives of 13N-substituted cytisine have been determined by X-ray diffraction. The two 13-acetyl substituted compounds, 3-bromo (1) and 3-iodo (2) are isostructural, with the isostructurality index as high as 99%. They both crystallize in monoclinic P2 1 space group, with unit cell parameters of a = 8.4709(10) Å , b = 9.2266(12) Å , c = 8.6051(10) Å , b = 98.528 (11)8 (1) and a = 8.2322(6) Å , b = 9.1724(7) Å , c = 8.5494(6) Å , b = 98.181 (7)8 (2). In turn, 3-bromo-13-t-butyl-carbonate derivative (3) crystallizes in orthorhombic P2 1 2 1 2 1 space group with a = 6.8171(3) Å , b = 7.8994(4) Å , c = 31.4657(15) Å . Conformation of the cytisine skeleton is similar in all three molecules, with almost planar A ring, sofa conformation of B-ring and C ring being an almost ideal chair. However, the orientations of the double C=O bonds in 13N-substituents are completely different: in 1 and 2 it is cis with respect to C12 (C12-N13-C14-O15 torsion angle is 3.3(4)8 in 1 and 1.3(6)8 in 2) while in 3 it is trans (-175.4(3)8). In the structures of 1 and 2 the driving force of the crystal architecture are quite strong C-HÁÁÁX halogen bonds with CÁÁÁX distances far shorter than the sums of van der Waals radii (CÁÁÁBr in 1 is 2.9430(19) Å and CÁÁÁI in 2 2.974(3)). In contrast in 3-partially as the consequence of different orientation of the substituent-there are no halogen bondings but instead some weak C-HÁÁÁO contacts organize the molecules into two-dimensional patterns.

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“…A recent report on the docking pose of cytisine at the a 4 b 2 nicotinic AChR [8] has evidenced a narrow channel connecting the ligand with the protein surface near C(4) (systematic atom numbering) of Cyt. Extrapolating for its proximity to the substituted N-atom of cytisine, in the examined compounds, we could correlate their different binding data considering the flexible chains of 1 and 2 to be positioned in the channel, but not those of the second cytisine of 3.…”

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confidence: 98%

“…2 and 3, respectively. They are characterized by the same conformation of the cytisine moiety, with the pyridinone ring A almost planar and ring B in envelope conformation (C(8) out of plane by À 0.722(7) and À 0.744 (8) for the two molecules of 1 and by À 0.735(9) for 2). In ring C with chair conformation, N(2) is at the vertex of a flattened pyramid with the lone pair in a position axial to ring C. Compound 1 is constituted by two molecules differing slightly for the orientation of the substituent at N(2), with torsional angles C(7)ÀN(2)ÀC(12)ÀC (13) The X-ray analysis of compound 3 has shown the two cytisine moieties bound through an ethylene bridge in two different orientations (Fig.…”

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confidence: 99%

The Influence of the Nitrogen Substitution in Three Cytisine Derivatives as Ligands for the Neuronal nAChRs: A Structural and Theoretical Study

Bombieri

Meneghetti

Artali

et al. 2008

Chemistry & Biodiversity

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Three cytisine derivatives, (-)-(7R,9S)-1-phenyl-3-(cytisin-12-yl)propan-1-one (1), (-)-(7R,9S)-1-phenyl-2-(cytisin-12-yl)ethane (2), and (-)-(7R,9S)-1,2-bis(cytisin-12-yl)ethane (3), with different electronic and steric features have been characterized by X-ray analysis and theoretical calculations in order to evaluate how structural modulations affect the intrinsic binding affinity at the neuronal nicotinic receptors (nAChRs). The crystal structures of 1 and 2, which display comparable affinities, are characterized by the same conformation of the cytisine moiety with different orientations of the substituent at N2. In 3, two independent molecules have the pyridinone rings diversely oriented. This compound has a lower affinity with respect to 1 and 2, but it increases the expression of neuronal nAChRs. Compounds 1, 2, and 3 retain the key prerequisite of the classical pharmacophoric models, with sp(3)-N-atom--HBA distances close to the expected value, both in solid state and in solution (theoretical calculations), where, in contrast with the extended in the crystal state, a curled-up conformation has been found, though maintaining the N-substituent in equatorial position.

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Chemical Medicine: Novel 10‐Substituted Cytisine Derivatives with Increased Selectivity for α4β2 Nicotinic Acetylcholine Receptors

Cited by 26 publications

References 58 publications

Structural Characterization of Binding Mode of Smoking Cessation Drugs to Nicotinic Acetylcholine Receptors through Study of Ligand Complexes with Acetylcholine-binding Protein

Structural Characterization of Binding Mode of Smoking Cessation Drugs to Nicotinic Acetylcholine Receptors through Study of Ligand Complexes with Acetylcholine-binding Protein

The Role of Halogen Bonding in Crystal Structures of 3-Halogeno Cytisine Derivatives

The Influence of the Nitrogen Substitution in Three Cytisine Derivatives as Ligands for the Neuronal nAChRs: A Structural and Theoretical Study

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