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. 2014 Jan 29;5(4):358-62.
doi: 10.1021/ml4004843. eCollection 2014 Apr 10.

Enhancing a CH-π Interaction to Increase the Affinity for 5-HT1A Receptors

Jean-François Liégeois  1 , Marc Lespagnard  1 , Elsa Meneses Salas  1 , Floriane Mangin  1 , Jacqueline Scuvée-Moreau  2 , Sébastien Dilly  3
Affiliations

Enhancing a CH-π Interaction to Increase the Affinity for 5-HT1A Receptors

Jean-François Liégeois et al. ACS Med Chem Lett. .

Abstract

An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible reinforcement of this interaction to increase the affinity for 5-HT1A receptors, different 4-substituted-phenyl analogues were synthesized and tested. The most important increase of affinity is obtained with two electron-donating methyl groups in positions 3 and 5.

Keywords: CH−π interaction; arylpiperazine; carboxamide; docking; electron-donating; quinoxaline.

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Figures

Scheme 1
Scheme 1
Figure 1
Figure 1
Binding mode of compounds 4a, 4b, 4k, and 4l (C, N, O, and H atoms in magenta, blue, red, and cyan, respectively) in a human 5-HT1A receptor agonist model. The hydrogen bonds are indicated by yellow dashed lines.
Figure 2
Figure 2
Electrostatic potential of compounds 4a (top left), 4b (top right), 4k (bottom left), and 4l (bottom right). The electrostatic map shows the electron-rich (purple) to the electron-deficient (red) regions of the compounds.
See this image and copyright information in PMC

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