Synthesis of Two Testosterone Derivatives and their Theoretical Evaluation as Serotonin Reuptake Transporter Inhibitors

This investigation aimed to synthesize two testosterone derivatives (4 and 7) from either testosterone 3-oxime or testosterone 3-(O-carboxymethyl)oxime. The chemical structure of the compounds was determined using nuclear magnetic resonance spectra. Besides, testosterone derivatives' theoretical activity on serotonin transporter (5i6z protein) was evaluated using fluoxetine as a control in a Docking model. The results showed a higher interaction of both compounds 4 and 7 with a 5i6z protein surface compared with fluoxetine. In conclusion, it's noteworthy that reagents used in this investigation no require special conditions. Also, the theoretical study showed that either compounds 4 or 7 could be good serotonin transporter inhibitors.

Gut Barrier Proteins Mediate Liver Regulation by the Effects of Serotonin on the Non-Alcoholic Fatty Liver Disease

: Serotonin (5-hydroxytryptamine, 5-HT) has been recognized as a potent pro-inflammatory mediator. Increasing the bioavailability and preventing the formation of 5-HT can reduce the inflammatory response in the body. Moreover, 5-HT is considered as an important central physiologic mediator of intestinal function by regulating intestinal motility, permeability, and other functions. The dysfunction of intestinal serotonergic system causes intestinal barrier damage and further leads to the increase of bacterial endotoxin (LPS) translocation into the liver, which contributes to the development of non-alcoholic fatty liver disease (NAFLD). In addition, increasing the expression of serotonin reuptake transporter (SERT) and decreasing the expression of tryptophan hydroxylase1 (TPH1) can relieve the symptoms of NAFLD. Tryptophan (TRP), as a precursor of 5-HT synthesis, plays an important role in gut homeostasis and energy metabolism. Previous studies have found that TRP supplementation aggravates fatty liver degeneration by producing 5-HT, which activates mTOR signaling pathway in mice fed a high fat and high fructose diet. However, recent researches reveal that TRP supplementation stabilizes the intestinal barrier damage by increasing the expression of occludin and reduces the accumulation of fatty acids in liver. Although the effects of TRP supplementation on NAFLD are not clear and the specific mechanism needs to be further explored. A better understanding of the mechanisms of 5-HT on the liver and gut may open new therapeutic strategies in NAFLD.

The serotonin reuptake transporter is reduced in the epithelium of active Crohn’s disease and ulcerative colitis

The serotonin reuptake transporter is potently reduced in inflamed areas of Crohn’s ileitis, Crohn’s colitis, and ulcerative colitis. The changes are localized to the intestinal epithelium and can be induced by TNF-α. The serotonin synthesis through tryptophan hydroxylase 1 is unchanged. This regulation is suggested as a mechanism underlying the increased extracellular serotonin levels associated with intestinal inflammation.

Acetylcholine Signaling Genes are Required for Cocaine-Stimulated Egg Laying in Caenorhabditis elegans

Despite the toxicity and addictive liability associated with cocaine abuse, its mode of action is not completely understood, and effective pharmacotherapeutic interventions remain elusive. The cholinergic effects of cocaine on acetylcholine receptors, synthetic enzymes, and degradative enzymes have been the focus of relatively little empirical investigation. Due to its genetic tractability and anatomical simplicity, the egg laying circuit of the hermaphroditic nematode, Caenorhabditis elegans, is a powerful model system to precisely examine the genetic and molecular targets of cocaine in vivo. Here, we report a novel cocaine-induced phenotype in Caenorhabditis elegans, cocaine-stimulated egg laying. In addition, we present the results of an in vivo candidate screen of synthetic enzymes, receptors, degradative enzymes, and downstream components of the intracellular signaling cascades of the main neurotransmitter systems that control Caenorhabditis elegans egg laying. Our results show that cocaine-stimulated egg laying is dependent on acetylcholine synthesis and synaptic release, functional nicotinic acetylcholine receptors, and the Caenorhabditis elegans acetylcholinesterases. Further, we show that cocaine-stimulated egg laying is not dependent on other neurotransmitters besides acetylcholine, including serotonin, dopamine, octopamine, and tyramine. Finally, our data show that cocaine-stimulated egg laying is increased in mutants for the C. elegans serotonin reuptake transporter as well as mutants for a 5-HT-gated chloride channel likely expressed in the locomotion circuit. Together, these results highlight serotonergic inhibition of egg laying behavior, functional connectivity between the egg laying and locomotion circuits in Caenorhabditis elegans, and possible discrete cholinergic and serotonergic effects of cocaine in the egg laying and locomotion circuits, respectively.

Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis

Purpose To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. Methods We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different “SS reporting zones” were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). Results Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). Discussion Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

The binding mode of vilazodone in the human serotonin transporter elucidated by ligand docking and molecular dynamics simulations

Vilazodone is a novel antidepressant for the treatment of major depressive disorder with the action mechanism of inhibiting the human serotonin reuptake transporter (hSERT), not only occupying the S1 binding site, but also extending to the S2 site.

Functional polymorphism of the serotonin reuptake transporter SLC6A4 gene in various clinical variants of irritable bowel syndrome

Rationale: Irritable bowel syndrome (IBS) is a multifactorial disease, the genetic aspect of which is being actively studied.Aim: To investigate functional polymorphism of the serotonin reuptake transporter (SERT) SLC6A4 gene of various clinical variants of IBS.Materials and methods: We performed a cross-sectional single center study in 79 Caucasian patients with IBS (according to the Rome criteria IV). The patients were divided into two groups: group 1, IBS with diarrhea (IBS-D, n = 45) and group 2, IBS with constipation (IBS-C, n = 34). The control group included 59 Caucasian patients with gastrointestinal disorders without IBS. Polymorphism 5-HTTLPR of the SLC6A4 gene was assessed in all subjects. In group 1 patients, blood serotonin levels were measured and psychological tests were performed, including Spielberger's State / Trait Anxiety Inventory, quality of life by SF36 and GSRS, Asthenia scale, VAS scores for pain intensity.Results: Thirty-five of 45 (77.8%) patients with IBS-D carried the mutant S allele, which was significantly more frequent than in the IBS-C group (p = 0.002) and in the control group (p = 0.005). There were no statistically significant differences (p = 0.54) in the frequency of detection of the homozygous LL genotype (normal allele) and the heteroand homozygous mutant alleles (SL and SS) genotype between the IBS-C and control patients. In the IBS-D group, a gender difference for the mutant SS allele of 5-HTTLPR was found, with significantly higher frequency in female patients (p = 0.0147). No significant gender differences in the genotype distribution between the patients with IBS-C and the control group were found. There were also no differences in blood serotonin levels in the IBS patients with various 5-HTTLPR types (p = 0.086); they were all in the reference range. However, there was a trend towards lower serotonin levels in the LL genotype carriers compared to those with the SS/SL polymorphisms. The Gastroenterological inventory GSRS demonstrated significantly higher total score for the constipation syndrome in the patients with homozygous LL 5-HTTLPR polymorphism, compared to that in the patients with the SS/SL genotype (p = 0.013).Conclusion: The results may be related to lower expression of the SLC6A4 gene in the carriers of the mutant allele in the 5-HTTLPR promoter and subsequent decreased rate of serotonin uptake, with resulting stimulation of the gastrointestinal tract. The SERT polymorphism of the SLC6A4 gene is worth further investigation as a potential candidate gene in the IBS pathophysiology.

Serotonin transporter deficiency alters socioemotional ultrasonic communication in rats

It has been widely established that serotonin plays important role in the regulation of emotional and social behaviour. Rodents with a genetic deletion of the serotonin reuptake transporter (SERT) are used as a model to study lifelong consequences of increased extracellular 5‐HT levels due to its impaired reuptake. SERT knock-out (SERT-KO) mice and rats consistently showed anxiety-like symptoms and social deficits. Nevertheless, the impact of SERT deletion on socioemotional ultrasonic communication has not been addressed. Here we investigated the impact of lifelong serotonin abundance on ultrasonic vocalisation accompanying social interactions and open field exploration in rats. SERT-KO rats displayed reduced overall duration of social contacts, but increased time spent on following the conspecific. The altered pattern of social behaviour in SERT-KO rats was accompanied by the structural changes in ultrasonic vocalisations, as they differed from their controls in distribution of call categories. Moreover, SERT deletion resulted in anxiety-like behaviours assessed in the open field test. Their anxious phenotype resulted in a lower tendency to emit appetitive 50-kHz calls during novelty exploration. The present study demonstrates that genetic deletion of SERT not only leads to the deficits in social interaction and increased anxiety but also affects ultrasonic communication.