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

Poupaert, Jacques;Gbaguidi, Fernand A.;Kapanda Nankwa, Coco;Aichaoui, Hocine;McCurdy, Christopher R.
(2013) Medicinal Chemistry Research : an international journal for rapid communications on design and mechanisms of action of biologically active agents — Vol. 22, n° 1, p. 247-252 (2013)

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Authors
  • Poupaert, JacquesUCLouvain
    Author
  • 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
    Author
  • Kapanda Nankwa, CocoUCLouvain
    Author
  • Aichaoui, HocineEquipe de Chimie Pharmaceutique Département de Chimie Faculté des Sciences, Université Badji-Mokhtar, Annaba, Algeria
    Author
  • McCurdy, Christopher R.Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, USA
    Author
Abstract
Based on a line of evidence (logP, pKa, <sup>1</sup>H-, and <sup>13</sup>C-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.
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Poupaert, J., Gbaguidi, F. A., Kapanda Nankwa, C., Aichaoui, H., & McCurdy, C. R. (2013). Is cocaine a social drug? Exploration of the stereo-structure of cocaine’s pharmacophore. Medicinal Chemistry Research : an international journal for rapid communications on design and mechanisms of action of biologically active agents, 22(1), 247-252. https://doi.org/10.1007/s00044-012-0005-2 (Original work published 2013)