title: Conformational analysis of cyproheptadine hydrochloride.
abstract: A nuclear magnetic resonance and theoretical study on the conformations and molecular flexibility of cyproheptadine hydrochloride (1) is reported. In the 1H NMR spectrum of 1 in CDCl3, two conformational forms are observed to occur in an approximate ratio of 1:4. In both forms, NOE and coupling constant measurements suggested that the terminal N-methyl group is equatorial. NOE experiments identified the more populated conformer (labeled D) as similar to the form seen in the X-ray crystal structure of cyproheptadine. The other form observed (A) may in principle be converted to D via either inversion of the central ring (T(inv)) or concerted nitrogen (N(inv)) and piperidine ring inversion (P(inv)). Chemical-exchange peaks in the 400-MHz 2D NOESY/chemical-exchange spectrum suggested that the latter mechanism is responsible for interconversion between the two forms. A theoretical study of the various interconversion processes using both molecular mechanics (MM2) and molecular orbital (AM1) approaches is also reported.
authors.affiliation: School of Pharmaceutical Chemistry, Victorian College of Pharmacy Ltd., Parkville, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Sadek
authors.forename: D J
authors.initials: DJ
authors.lastname: Craik
authors.forename: J G
authors.initials: JG
authors.lastname: Hall
authors.forename: P R
authors.initials: PR
authors.lastname: Andrews
mesh_terms: D055598:Chemical Phenomena; D002621:Chemistry; D003533:Cyproheptadine; D015195:Drug Design; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013237:Stereoisomerism
chemical_list: D003533:Cyproheptadine