Benzimidazole Derivatives as New Serotonin 5-HT₆ Receptor Antagonists. Molecular Mechanisms of Receptor Inactivation

Abstract

On the basis of our previously described pharmacophore model for serotonin 5-HT(6) receptor (5-HT(6)R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1-20 that represent a new family of potent antagonists at the human 5-HT(6)R. Site-directed mutagenesis and a beta(2)-adrenoceptor-based homology model of the 5-HT(6)R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH(2)-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT(6)R antagonists.

Pyrano[2,3,4-cd]indole as a Scaffold for Selective Nonbasic 5-HT6R Ligands

“…The binding mode of the synthesized compounds was investigated with docking experiments to the homology models of 5-HT 6 R (see Supporting Information). Both the basic and nonbasic analogues exhibited very consistent binding modes (Figure 2), overlapping with the previously reported data: 23 the peripheral aromatic group formed stacking interactions with phenylalanines F 6×51 and F 6×52 , and the sulfonyl group of the ligands formed a hydrogen bond with N 6×55 , in line with the mutagenetic data. 24 In addition, a protonated nitrogen atom of the basic analogues formed a charge-assisted hydrogen bond with D 3×32 , exhibiting the classical binding mode for the basic compounds.…”

Therapeutic Potential of 5-HT6 Receptor Agonists

“…5-HT binds closely to the TM3− TM6 region, thus engaging a further interaction with TM5 Thr 5.46 , while the antagonist is proposed to bind to the TM6, TM7, and TM1 regions. Another hypothesis has recently been proposed by de la Fuente et al 32 to explain the inactivation of the receptor by the antagonist. Beginning with the general consideration of GPCR activation occurring through TM helix dynamics 33 and because of site-directed mutagenesis, the authors have proposed a basis for the molecular mechanism underlying 5-HT 6 R inactivation.…”

A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding

“…Representative ligand 1 ( K i  = 34 nM) contains 4-methylpiperazine moiety as PI pharmacophore element, a carbonyl group as HBA, and a naphthalene ring as HYD (Fig. 1B)9. In the present work we further explore the benzimidazole system as a central scaffold to identify 5-HT 6 R antagonists.…”