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.
Highlights
The development of new 5-HT6 receptor (5-HT6R) antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer’s disease (AD)
The decrease of the antagonist activity of compound 7 when the C1103.36, S1935.43, F2856.52, and N2886.55 were mutated to Ala (Fig. 5B) validated the predicted binding mode to the 5-HT6R and supported the backbone carbonyl group of A1574.56 as the putative binding partner for the halogen atom
Combined site-directed mutagenesis and computational studies of this class of antagonists in complex with the 5-HT6R expand our pharmacophore model; in addition to the four key structural elements —PI, AR, HBA, and HYD, we propose the importance of a halogen atom attached to the HYD moiety to form a halogen bond with the free carbonyl group at position 4.56 (Fig. 5E)
Summary
The development of new 5-HT6R antagonists is still needed to validate these molecules as a drug class for the treatment of AD. Structure-activity relationship studies as well as complementary methodologies of drug design, such as pharmacophore-based and structure-based homology models, have allowed the identification of four common key structural elements in 5-HT6R antagonists (Fig. 1A): a positive ionisable atom (PI, in red), an aromatic ring (AR, in yellow), a hydrogen bond acceptor group (HBA, in green), and a hydrophobic site (HYD, in blue)[8]. As part of our efforts to develop 5-HT6R antagonists, we have previously contributed with a new family of compounds based on a benzimidazole ring as central AR core. Structural information of the 5-HT6R is presently unavailable, the recently provided crystallographic data for the serotonin 5-HT1B and 5-HT2B receptors[10,11] and mutagenesis studies have been used to develop molecular models of the 5-HT6R in complex with the synthesized compounds, which have shown the importance of a halogen bond interaction in the HYD element to stabilize the binding.
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