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Title

X-ray crystal structure, partitioning behavior, and molecular modeling study of piracetam-type nootropics: insights into the pharmacophore

Authors
Altomare, Cosimo
Cellamare, S.
Carotti, Angelo
Casini, G.
Ferappi, M.
Gavuzzo, E.
Mazza, F.
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Published in Journal of Medicinal Chemistry. 1995, vol. 38, no. 1, p. 170-179
Abstract 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.
Keywords Chemistry, PhysicalCrystallography, X-RayLipids/chemistryMagnetic Resonance SpectroscopyModels, MolecularMolecular ConformationMolecular StructureNootropic Agents/*chemistryPhysicochemical PhenomenaPiracetam/*chemistrySolubilityStereoisomerismStructure-Activity Relationship
Stable URL http://archive-ouverte.unige.ch/unige:10531
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Other version: http://pubs.acs.org/doi/pdf/10.1021/jm00001a022
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PMID: 7837228
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