Pyrroloquinoline scaffold-based 5-HT6R ligands: Synthesis, quantum chemical and molecular dynamic studies, and influence of nitrogen atom position in the scaffold on affinity

Computer-Aided Studies for Novel Arylhydantoin 1,3,5-Triazine Derivatives as 5-HT6 Serotonin Receptor Ligands with Antidepressive-Like, Anxiolytic and Antiobesity Action In Vivo

“…Molecular docking was performed to gain an insight into the binding mode of the library of compounds synthetized ( 5 – 26 ) to the recently developed 5-HT 6 R homology models [ 13 ] built on the β 2 adrenergic receptor template and optimized for the structures of Lead 1 and 2. The molecular docking indicated that newly synthesized compounds, generally, exhibited a very consistent binding mode with recently reported 5-HT 6 ligands [ 16 , 17 , 18 ]. An influence of the topology of aromatic substituents and the position of the 1,3,5-triazine substitution at the hydantoin ring on the binding has been observed ( Figure 2 ) and was in good agreement with results of the radioligand binding assay (see below).…”

Dual 5-HT6 and D3 Receptor Antagonists in a Group of 1H-Pyrrolo[3,2-c]quinolines with Neuroprotective and Procognitive Activity

“…We next focused on the influence of the kind of the alkyl substituent on the basic nitrogen atom of pyrrolidine of CPPQ on the receptors affinity. Taking into account the important role of halogen bonding in the interaction with various GPCRs, and specifically the 5-HT 6 R, [26][27][28] the chlorine atom was removed from the arylsulfonyl fragment. This modification confirmed the strong contribution of halogen bonding for binding to the 5-HT 6 R (21 vs 14).…”

“…The choice also resulted from preferential role of chlorine atom in stabilization of the ligand-receptor complex by the halogen bonding. [26][27][28] Finally, to investigate the stereochemical preference of designed derivatives, four pairs of enantiomers were tested. The influence of applied modifications on 5-HT 6 /D 3 Rs affinity was first tested in in vitro studies, supported by in silico analysis.…”

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

“…The 5-HT6R homology models were obtained according to the procedure described before on the β2 receptor template and successfully used in our earlier studies of different groups of 5-HT6R ligands simulations. 48,49 The structure of monoamine oxidases B (PDB code 2C65) 38 in complex with irreversible inhibitor rasagilline analog those with a coherent binding mode. 50 The 3-dimensional structures of the ligands were obtained using LigPrep v3.6, 51 and the appropriate ionization states at pH = 7.4±1.0 were assigned using Epik v3.4.…”