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Is cocaine a social drug? Exploration of the stereo-structure of cocaine's pharmacophore

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Poupaert, Jacques [UCL] Gbaguidi, Fernand A. [Laboratoire de Pharmacognosie, Centre Beninois de Recherche Scientifique et Technique, Faculté des Sciences et Techniques, Université d’Abomey-Calavi, Porto-Novo, Benin] Kapanda Nankwa, Coco [UCL] Aichaoui, Hocine [Equipe de Chimie Pharmaceutique Département de Chimie Faculté des Sciences, Université Badji-Mokhtar, Annaba, Algeria] McCurdy, Christopher R. [Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, USA]

Based on a line of evidence (logP, pKa, 1H-, and 13C-NMR, and molecular modeling studies), it appears that cocaine undergoes a hydrophobic collapse which may account for its unprecedented ADME properties, in particular, its exceptional capacity to cross biological membranes. Using molecular simulation techniques, the hypothesis of hydrophobic collapse undergone by the protonated form of cocaine was substantiated using semi-empirical quantum calculations (mainly AM1 and PM3) performed as well as ab initio quantum calculations (6-31 G**). A molecular electrostatic potential map of the internally hydrogen-bonded structure was acquired under AM1 and showed a continuum of high electron density in the central part of the molecule around the methyl ammonium and the two ester moieties. This picture is consistent with the picture of the ammonium being locked between the two C=O and forming a strong canonical primary H bond with the methyl ester and a weaker secondary H bond (non-canonical) with the benzoate ester. Cocaine represents the prototypical example of molecular concision because the pharmacophore and the vector are embedded in the same molecular scaffold. © 2012 Springer Science+Business Media, LLC.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2013
Language Anglais
Journal information "Medicinal Chemistry Research : an international journal for rapid communications on design and mechanisms of action of biologically active agents" - Vol. 22, no. 1, p. 247-252 (2013)
Peer reviewed yes
Publisher Birkhaeuser Boston
e-issn 1554-8120
issn 1054-2523
Publication status Publié
Affiliation UCL - SSS/LDRI - Louvain Drug Research Institute
Links
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Bibliographic reference Poupaert, Jacques ; Gbaguidi, Fernand A. ; Kapanda Nankwa, Coco ; Aichaoui, Hocine ; McCurdy, Christopher R.. Is cocaine a social drug? Exploration of the stereo-structure of cocaine's pharmacophore. In: Medicinal Chemistry Research : an international journal for rapid communications on design and mechanisms of action of biologically active agents, Vol. 22, no. 1, p. 247-252 (2013)
Permanent URL http://hdl.handle.net/2078.1/160708