The influence of the nitrogen substitution in three cytisine derivatives as ligands for the neuronal nAChRs: a structural and theoretical study.
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.
Bombieri
Gabriella
G
Istituto di Chimica Farmaceutica e Tossicologica 'P. Pratesi', Università di Milano, Via L. Mangiagalli, 25, I-20133 Milano.
Meneghetti
Fiorella
F
Artali
Roberto
R
Tasso
Bruno
B
Canu Boido
Caterina
C
Sparatore
Fabio
F
D000470:Alkaloids / Q000737:chemistry*; D001392:Azocines / Q000737:chemistry; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D011807:Quinolizines / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012997:Solvents; D013329:Structure-Activity Relationship; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D008024:Ligands; D009584:Nitrogen; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012997:Solvents; C004712:cytisine; D000093843:Quinolizidine Alkaloids