Predicting biological activity and design of 5-HT6 antagonists through assessment of ANN-QSAR models in the context of Alzheimer's disease.

CONTEXT: Alzheimer's disease (AD) is the leading cause of dementia around the world, totaling about 55 million cases, with an estimated growth to 74.7 million cases in 2030, which makes its treatment widely desired. Several studies and strategies are being developed considering the main theories regarding its origin since it is not yet fully understood. Among these strategies, the 5-HT6 receptor antagonism emerges as an auspicious and viable symptomatic treatment approach for AD. The 5-HT6 receptor belongs to the G protein-coupled receptor (GPCR) family and is closely implicated in memory loss processes. As a serotonin receptor, it plays an important role in cognitive function. Consequently, targeting this receptor presents a compelling therapeutic opportunity. By employing antagonists to block its activity, the 5-HT6 receptor's functions can be effectively modulated, leading to potential improvements in cognition and memory. METHODS: Addressing this challenge, our research explored a promising avenue in drug discovery for AD, employing Artificial Neural Networks-Quantitative Structure-Activity Relationship (ANN-QSAR) models. These models have demonstrated great potential in predicting the biological activity of compounds based on their molecular structures. By harnessing the capabilities of machine learning and computational chemistry, we aimed to create a systematic approach for analyzing and forecasting the activity of potential drug candidates, thus streamlining the drug discovery process. We assembled a diverse set of compounds targeting this receptor and utilized density functional theory (DFT) calculations to extract essential molecular descriptors, effectively representing the structural features of the compounds. Subsequently, these molecular descriptors served as input for training the ANN-QSAR models alongside corresponding biological activity data, enabling us to predict the potential efficacy of novel compounds as 5-hydroxytryptamine receptor 6 (5-HT6) antagonists. Through extensive analysis and validation of ANN-QSAR models, we identified eight new promising compounds with therapeutic potential against AD.

1-Boc-Piperidine-4-Carboxaldehyde Prevents Binge-Eating Behaviour and Anxiety in Rats.

BACKGROUND: Piperidines are biogenic amines studied mainly in toxicology because they were initially found as alkaloids from peppers and insect venoms. Piperidines are also produced in the human body, and their actions seem to be related to wakefulness/sleep and other cognitive phenomena. Piperidines have been minimally characterized for therapeutic applications. In this context, 1-Boc-piperidine-4-carboxaldehyde (1-Boc-piperidine) is a piperidine-derivative molecule with no mechanism of action reported, although its uses include the synthesis of GPR119 selective agonists that have been patented as anti-obesity drugs. OBJECTIVES: The aim of this work was to study the effects of 1-Boc-piperidine on binge-eating behaviour and anxiety in Wistar rats. METHODS: In experimental protocol 1, binge-eating behaviour was induced in animals that received pre-treatment (i.p.) with (i) vehicle (methanol 10%; 1 mL/kg), (ii) 1-Boc-piperidine (1 µmol kg-1), or (iii) 1-Boc-piperidine (10 µmol kg-1). In experimental protocol 2, mildly stressed animals were evaluated in the elevated plus maze under the acute effects of the pre-treatments applied in experimental protocol 1. RESULTS AND CONCLUSIONS: 1-Boc-piperidine decreased, in a dose-dependent manner, the intake of calories from a succulent hyper-caloric food in a binge-eating protocol in female rats, whereas the acute exposition to this piperidine exerted an anxiolytic effect in the male rat. In both effects, the mechanism of action remains to be characterized.

Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation.

Based on a known pharmacophore model for 5-HT6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT6 receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay.

Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: involvement of 5-HT7 receptors.

Serotonin (5-HT) modulates the hypothalamic-pituitary-adrenal (HPA) axis response to stress. We examined the effect of chronic restraint stress (CRS; 20 min/day) as compared to control (CTRL) conditions for 14 days, on: 1) restraint-induced ACTH and corticosterone (CORT) secretion in rats pretreated with vehicle or SB-656104 (a 5-HT7 receptor antagonist); 2) 5-HT7 receptor-like immunoreactivity (5-HT7-LI) and protein in the hypothalamic paraventricular nucleus (PVN) and adrenal glands (AG); 3) baseline levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA), and 5-HIAA/5-HT ratio in PVN and AG; and 4) 5-HT-like immunoreactivity (5-HT-LI) in AG and tryptophan hydroxylase (TPH) protein in PVN and AG. On day 15, animals were subdivided into Treatment and No treatment groups. Treatment animals received an i.p. injection of vehicle or SB-656104; No Treatment animals received no injection. Sixty min later, Treatment animals were either decapitated with no further stress (0 min) or submitted to acute restraint (10, 30, 60 or 120 min); hormone serum levels were measured. No Treatment animals were employed for the rest of measurements. CRS decreased body weight gain and increased adrenal weight. In CTRL animals, acute restraint increased ACTH and CORT secretion in a time of restraint-dependent manner; both responses were inhibited by SB-656104. Exposure to CRS abolished ACTH but magnified CORT responses to restraint as compared to CTRL conditions; SB-656104 had no effect on ACTH levels but significantly inhibited sensitized CORT responses. In CTRL animals, 5-HT7-LI was detected in magnocellular and parvocellular subdivisions of PVN and sparsely in adrenal cortex. Exposure to CRS decreased 5-HT7-LI and protein in the PVN, but increased 5-HT7-LI in the adrenal cortex and protein in whole AG. Higher 5-HT and 5-HIAA levels were detected in PVN and AG from CRS animals but 5-HIAA/5-HT ratio increased in AG only. Finally, whereas 5-HT-LI was sparsely observed in the adrenal cortex of CTRL animals, it strongly increased in the adrenal cortex of CRS animals. No TPH protein was detected in AG from both animal groups. Results suggest that CRS promotes endocrine disruption involving decreased ACTH and sensitized CORT responses to acute restraint. This phenomenon may be associated with increased function and expression of 5-HT7 receptors as well as 5-HT turnover in AG.

Role of local anesthetics on both cholinergic and serotonergic ionotropic receptors.

A great body of experimental evidence indicates that the main target for the pharmacological action of local anesthetics (LAs) is the voltage-gated Na+ channel. However, the epidural and spinal anesthesia as well as the behavioral effects of LAs cannot be explained exclusively by its inhibitory effect on the voltage-gated Na+ channel. Thus, the involvement of other ion channel receptors has been suggested. Particularly, two members of the neurotransmitter-gated ion channel receptor superfamily, the nicotinic acetylcholine receptor (AChR) and the 5-hydroxytryptamine receptor (5-HT3R type). In this regard, the aim of this review is to explain and delineate the mechanism by which LAs inhibit both ionotropic receptors from peripheral and central nervous systems. Local anesthetics inhibit the ion channel activity of both muscle- and neuronal-type AChRs in a noncompetitive fashion. Additionally, LAs inhibit the 5-HT3R by competing with the serotonergic agonist binding sites. The noncompetitive inhibitory action of LAs on the AChR is ascribed to two possible blocking mechanisms. An open-channel-blocking mechanism where the drug binds to the open channel and/or an allosteric mechanism where LAs bind to closed channels. The open-channel-blocking mechanism is in accord with the existence of high-affinity LA binding sites located in the ion channel. The allosteric mechanism seems to be physiologically more relevant than the open-channel-blocking mechanism. The inhibitory property of LAs is also elicited by binding to several low-affinity sites positioned at the lipid-AChR interface. However, there is no clearcut evidence indicating whether these sites are located at either the annular or the nonannular lipid domain. Both tertiary (protonated) and quaternary LAs gain the interior of the channel through the hydrophilic pathway formed by the extracellular ion channel's mouth with the concomitant ion flux blockade. Nevertheless, an alternative mode of action is proposed for both deprotonated tertiary and permanently-uncharged LAs: they may pass from the lipid membrane core to the lumen of the ion channel through a hydrophobic pathway. Perhaps this hydrophobic pathway is structurally related to the nonannular lipid domain. Regarding the LA binding site location on the 5-HT3R, at least two amino acids have been involved. Glutamic acid at position 106 which is located in a residue sequence homologous to loop A from the principal component of the binding site for cholinergic agonists and competitive antagonists, and Trp67 which is positioned in a stretch of amino acids homologous to loop F from the complementary component of the cholinergic ligand binding site.