X-ray crystal structure, partitioning behavior, and molecular modeling study of piracetam-type nootropics: insights into the pharmacophore.
To detect possible molecular determinants of amnesia-reverting activity, the conformational properties of a number of rigid and flexible piracetam-type cognition enhancers have been assessed by X-ray diffraction, NMR spectroscopy, and ab initio and high-temperature-quenched molecular dynamics (QMD) calculations. The structures of the preferred conformers in solution derived from 1H-NMR spectral analysis were in good agreement with those found by QMD calculations. Interestingly, the calculation of the average molecular lipophilicity potential on the water-accessible surface of the selected conformers was helpful in interpreting the partitioning behavior observed by measuring octanol-water partition coefficients and capacity factors in reversed-phase high-performance liquid chromatography. While lipophilicity does not play a relevant role, the distance between polar groups, accounted for by the distance between carbonyl oxygens, emerges as a factor, among others, which should influence the amnesia-reversal activity of piracetam-type nootropics.
Dipartimento Farmaco-Chimico, University of Bari, Italy.
C
C
Altomare
S
S
Cellamare
A
A
Carotti
G
G
Casini
M
M
Ferappi
E
E
Gavuzzo
F
F
Mazza
P T
PT
Carrupt
P
P
Gaillard
B
B
Testa
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D018697:Nootropic Agents / Q000737:chemistry*; D010889:Piracetam / Q000737:chemistry*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008055:Lipids; D018697:Nootropic Agents; D010889:Piracetam