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

Altomare, Cosimo; Cellamare, S.; Carotti, Angelo; Casini, G.; Ferappi, M.; Gavuzzo, E.; Mazza, F.; Carrupt, Pierre-Alain; Gaillard, Patrick; Testa, Bernard

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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. Carrupt, Pierre-Alain Gaillard, Patrick Testa, Bernard show all authors [1 - 10]
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, Physical — Crystallography, X-Ray — Lipids/chemistry — Magnetic Resonance Spectroscopy — Models, Molecular — Molecular Conformation — Molecular Structure — Nootropic Agents/chemistry — Physicochemical Phenomena — Piracetam/chemistry — Solubility — Stereoisomerism — Structure-Activity Relationship
Identifiers		DOI: 10.1021/jm00001a022 PMID: 7837228
Full text		Article - Limited access to UNIGE Other version: http://pubs.acs.org/doi/pdf/10.1021/jm00001a022
Citation (ISO format)		ALTOMARE, Cosimo et al. X-ray crystal structure, partitioning behavior, and molecular modeling study of piracetam-type nootropics: insights into the pharmacophore. In: Journal of Medicinal Chemistry, 1995, vol. 38, n° 1, p. 170-179. https://archive-ouverte.unige.ch/unige:10531