The 5-HT₆ receptor, which is localized practically only in the brain [1] is a promising target for different new psychotropic drugs. 5-HT₆ receptors are supposed to be responsible mainly for motor control, memory and learning and its antagonists can be used to improve cognitive and memory functions in cognitive impairments [2, 3, 4] and also as an antiobesity drugs [5, 6]. Up to date several thousands of structurally diverse ligands have been synthesized but their binding mode has not been fully identified.

During virtual screening campaign for the search of novel 5-HT₆R ligands, a 3-fold less active bioisostere of literature compound [7] was found. A series of its isosteres was synthesized in an attempt to increase affinity. One of this compounds proved to be 10-times more potent than the parent one. Crystal structures and molecular modeling studies justified structure-activity relationship.

References:

[1] Sleight, A. J.; Boess, F. G.; Bös, M.; Bourson, A. Ann. N. Y. Acad. Sci. 1998, 861, 91–6.

[2] Rossé, G.; Schaffhauser, H. Curr. Top. Med. Chem. 2010, 10, 207–21.

[3] Geldenhuys, W. J.; Schyf, C. J. Van der Expert Rev. Neurother. 2009, 9, 1073–85.

[4] Quiedeville, A.; Boulouard, M.; Silva Costa-Aze, V. Da; Dauphin, F.; Bouet, V.; Freret, T. Rev. Neurosci. 2014.

[5] Heal, D.; Gosden, J.; Smith, S. Int. Rev. Neurobiol. 2011, 96, 73–109.

[6] Garfield, A. S.; Burke, L. K.; Shaw, J.; Evans, M. L.; Heisler, L. K. Behav. Brain Res. 2014, 1–6.

[7] Tasler, S.; Kraus, J.; Wuzik, A.; Müller, O.; Aschenbrenner, A.; Cubero, E.; Pascual, R.; Quintana-Ruiz, J.-R.; Dordal, A.; Mercè, R.; Codony, X. Bioorg. Med. Chem. Lett. 2007, 17, 6224–9.

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