Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

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-HT 1A 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-HT 1A 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, quinoxaline, carboxamide, arylpiperazine, electron-donating, docking R ecently, we reported that a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue was shown to be favorable compared to the corresponding 4-phenyl-piperazine one in terms of affinity for 5-HT 1A receptors in a series of 4-arylpiperazine-ethyl carboxamides. 1 An electrostatic interaction between the distal benzene ring of the molecule and a phenylalanine residue (Phe 6.52) particularly in the 5-HT 1A receptor binding pocket was suggested by molecular modeling approaches. 2 The almost coplanar orientation of both rings displayed in the 4-phenyl-THP compound appeared as an important spatial requirement for an optimal interaction with the 5-HT 1A receptor in the present series. This orientation should stabilize the ligand binding by an edge-to-face CH−π interaction between the phenyl ring of the 4-phenyl-THP compounds and the phenyl ring of the Phe 6.52 residue. 2 This would explain why the chemical modification of the piperazine ring into THP is favorable for receptor affinity.The electron donating/withdrawing properties of an aromatic substituent is an important factor for the electron density of the aromatic ring and consequently for the capacity of these rings to be involved in aromatic stacking interactions. 3 Some studies have already shown the impact of the electronic properties of the substituents on the stability of these interactions in ligand−receptor binding. 4,5 Therefore, by increasing the electronic density with an electron-donating group, we expected to reinforce the interaction between the distal benzene ring and the Phe 6.52 residue. The substituents were positioned either in position 4 or positions 3 and 5 of the distal ring in order to avoid a sterical constraint if present in position 2 or 6. To explore a possible opposite effect linked to the electronic properties of the substituents, electron-withdrawing atoms were also introduced. The THP derivatives were tested, in parallel with the corresponding arylpiperazine derivatives, for their affinity for 5-HT 1A receptors. The intrinsic activity of six selected compounds was also investigated using an electrophysiological approach.The target compounds were prepared by reaction of the appropriate primary amine with the appropriate acyl chloride (2-naphthoyl chloride or 2-quinoxaline chloride) as reported in Scheme 1. The crude amines were synthesized following a Gabriel pro...

Development of selective agents targeting serotonin 5HT1A receptors with subnanomolar activities based on a coumarin core

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“…Additionally, all presented ligand poses exhibit the crucial interaction between the basic nitrogen atom of piperazine and D116, known to play a vital role in the stabilization of the ligands of this class in the binding pocket. 17 Based on the computational results we can try to rationalize the obtained experimental K i values. Fig.…”

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