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

Abstract

Serotonin 5-HT6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer’s disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT6 receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2B subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1 mg/kg, ip) in the novel object recognition task as a model of memory deficit.

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).…”

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

“…These studies also claim that 5-HT 6 R antagonists could improve cognitive functions; some agents are in the preclinical stage [74,75]. Many of these agents are associated with substantial improvements in different cognitive tasks and enhanced memory retention or formation in rodents [76]. To date, at least three candidates have already reached Phase II/III clinical trials as novel therapeutic agents for the treatment of AD [77].…”

“…Indeed, the serotonin receptor 5-HT 6 R is an attractive drug target for reversing memory loss and learning disabilities associated with NDDs [77][78][79]. A recent study has discovered a new benzimidazole-based compound that is an antagonist of 5-HT 6 R and improves the novel object identification task in memory-deficit mice [76].…”

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6receptor antagonists and beyond

“…[23][24][25]27,28 Based on docking study, it is postulated that it interacts with N6.55 and S5. 43 forming O-H/O and N-H/O bonds, 23,27,28 respectively. However, in the statistical approach applied for the majority of protein-ligand complexes deposited within the PDB (Protein Data Bank), the sulfonyl moiety is not involved in the strong hydrogen bond formation and usually occupies the hydrophobic pocket of the protein biding site.…”

“…[23][24][25][26][27][28] In the pharmacophore model of the 5-HT 6 R antagonists, the sulfonyl fragment is usually considered as the strong hydrogen bond acceptor. [23][24][25]27,28 Based on docking study, it is postulated that it interacts with N6.55 and S5. 43 forming O-H/O and N-H/O bonds, 23,27,28 respectively.…”