5-HT3 Receptor Research Articles

Management of Trastuzumab Deruxtecan-related nausea and vomiting in real-world practice.

Nausea and vomiting are common side effects of Trastuzumab Deruxtecan (T-DXd), but guidelines for optimal management were not initially available. This retrospective single-center study aimed at evaluating the efficacy of two antiemetic regimens in patients receiving T-DXd. Data from metastatic breast cancer patients receiving T-DXd were collected. Two groups were defined: patients treated with 5-HT3 receptor antagonists (RA) ± dexamethasone (5-HT3-group) and patients treated with a fixed oral combination of netupitant (NK1RA) and palonosetron ± dexamethasone (NK1 group). Physicians preferentially offered the NK1 regimen to patients at higher risk of nausea and vomiting based on internal recommendations. Only nausea and vomiting during cycles 1 and 2 were considered. Comparisons of nausea and vomiting by the antiemetic prophylaxis group were assessed using chi-square. A total of 53 patients were included in the analysis. At cycle 1, 72% and 28% of patients received the 5-HT3 and NK1 prophylaxis, respectively. Overall, 58% reported nausea, with no differences between groups (58% vs. 60%; p = 0.832), but with a trend for lower grade in the NK1 group (33.3% G1; 26.7% G2) compared to the 5-HT3 group (23.7% G1; 31.6% G2; 2.6% G3). Vomiting was reported by 21% and 0% of patients in the 5-HT3 and the NK1 group, respectively (p = 0.054). Among the 15 patients in the 5-HT3 group with nausea at cycle 1 who escalated to NK1 at cycle 2, nausea decreased from 100% to 53% (p = 0.022) and vomiting decreased from 47% to 13% (p = 0.046). The NK1 regimen improved vomiting control at cycle 1 and, when introduced at cycle 2, significantly improved both nausea and vomiting. The biased NK1 selection for higher-risk patients may have dampened the differences between groups at cycle 1. These findings support enhanced control of T-DXd-related nausea and vomiting with NK1RA.

Cholecystokinin-Induced Duodenogastric Bile Reflux Increases the Severity of Indomethacin-Induced Gastric Antral Ulcers in Re-fed Mice.

We examined the involvement of cholecystokinin (CCK) in the exacerbation of indomethacin (IND)-induced gastric antral ulcers by gastroparesis caused by atropine or dopamine in mice. Male mice were fed for 2h (re-feeding) following a 22-h fast. Indomethacin (IND; 10mg/kg, s.c.) was administered after re-feeding; gastric lesions were examined 24h after IND treatment. In another experiment, mice were fed for 2h after a 22-h fast, after which the stomachs were removed 1.5h after the end of the feeding period. Antral lesions, the amount of gastric contents, and the gastric luminal bile acids concentration were measured with or without the administration of the pro- and antimotility drugs CCK-octapeptide (CCK-8), atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, lorglumide (CCK1 receptor antagonist), ondansetron, and haloperidol alone and in combination. IND produced severe lesions only in the gastric antrum in re-fed mice. CCK-8, atropine, dopamine, SR57227 and apomorphine administered just after re-feeding increased bile reflux and worsened IND-induced antral lesions. These effects were significantly prevented by pretreatment with lorglumide. Although atropine and dopamine also increased the amount of gastric content, lorglumide had no effect on the delayed gastric emptying provoked by atropine and dopamine. Both ondansetron and haloperidol significantly inhibited the increase of bile reflux and the exacerbation of antral lesions induced by atropine and dopamine, respectively, but did not affect the effects of CCK-8. These results suggest that CCK-CCK1 receptor signal increases bile reflux during gastroparesis induced by atropine and dopamine, exacerbating IND-induced antral ulcers.

Comparison of prophylaxis strategy for postoperative nausea and vomiting and its incidence before and after the implementation of 5-hydroxytryptamine 3 in surgical setting: a single-center, retrospective study.

To investigate the association between adherence to guideline-recommended risk-based postoperative nausea and vomiting (PONV) prophylaxis, the antiemetics used for PONV prophylaxis, and the incidence of PONV in patients who were underwent general anesthesia before and after 5-HT3 receptor antagonists became available. Patients (≥ 20years old) who were extubated after scheduled surgery and returned to general wards between January 2021 and February 2022 and between June 2022 and July 2023 were included. Risk factors included age < 50, female, motion sickness, nonsmoker, surgical factors, and postoperative opioid use. Two and three or more prophylaxis were recommended for patients with one or two and three or more risk factors, respectively. The primary outcome was the number of patients who received adequate prophylaxis, and the secondary outcomes were antiemetic agents used during anesthesia and the incidence of PONV on postoperative days 0 and 1. PONV was defined as documented PONV or rescue antiemetic administration. From January 2021 to February 2022 and from June 2022 to July 2023, 2342 and 2682 patients were included, respectively. Before ondansetron became available, more D2 receptor antagonists were used (p < 0.001), and after ondansetron became available, both ondansetron (p < 0.001) and propofol (p < 0.001) were given more frequently. Before and after ondansetron became available, the number of patients with adequate prophylaxis was 3.7% and 9.2%, respectively (p < 0.001), and the incidence of PONV on postoperative days 0 and 1 was 44.6% and 44.0%, respectively (p = 0.67). The availability of ondansetron increased the number of patients with adequate PONV prophylaxis, but did not decrease the incidence of PONV.

Serotonergic neurotransmission mediated cognitive dysfunction in two mouse models of sepsis-associated encephalopathy.

Patients with sepsis-associated encephalopathy (SAE) often exhibit cognitive impairments. Despite this, the underlying mechanisms of SAE remain largely unexplored. Here, we explored the role of serotonergic neurotransmission in cognitive dysfunction of two mouse models of SAE. The mouse models of SAE were established by injection of lipopolysaccharide (LPS, 10 mg/kg, intraperitoneal) and cecal ligation puncture (CLP) respectively. Barnes maze, new object recognition test and open field test were used to evaluate the effects of fluoxetine (selective serotonin reuptake inhibitor) and cyproheptadine (nonselective 5-HT2 receptor antagonist) on cognition and motor activity of mice. Additionally, WAY100635 (5-HT1A receptor antagonist) was co-administered with fluoxetine to explore the mechanism underlying effect of fluoxetine on cognitive impairments of SAE. Enzyme-linked immunosorbent assay (ELISA) was performed to determine 5-HT levels in hippocampus, brainstem and frontal lobe of experimental groups. Both LPS-induced sepsis and CLP induced sepsis resulted in a notable learning deficit. Fluoxetine ameliorated, while cyproheptadine aggravated, cognitive impairment in two classic mouse models of SAE. The cognition-enhancing effect of fluoxetine is reversed by WAY100635. Decreased 5-HT levels in hippocampus, brainstem and frontal lobe were observed in LPS septic model and CLP septic model. Notably, both fluoxetine and cyproheptadine significantly increased 5-HT levels in those brain regions in LPS septic model. Additionally, fluoxetine significantly increased 5-HT levels in frontal lobe of CLP septic model. Our study demonstrated that serotonergic neurotransmission plays a significant role in mechanisms underlying cognitive impairment in SAE. These findings contribute to identification of novel targets to prevent and arrest cognitive impairment in SAE.

Can Serotonin 7 Receptors Be a Treatment Target for Noncentral Diseases?

The neurotransmitter serotonin (5-HT) is involved in several key processes in the central nervous system. But the great majority of serotonin is produced by intestinal enterochromafn cells of the gastrointestinal (GI) tract and circulating blood platelets, which work independently of the central nervous system. The mediating pathway through which serotonin transmits its efects is the 5-HT receptor (5-HTR) superfamily, which consists of at least 14 members with extensive characterizations. Having been discovered as the final member of the 5-HTR family, 5-HT7 receptors have specific roles in the neurological, GI, circulatory, and immune systems. Due to their extensive distribution, these receptors' stimulation and repression are of importance during the therapy process, even if their exact mechanism of action in disease has not been fully understood. This review establishes the functions of 5-HT7Rs in systems and discusses how these receptors may be used therapeutically to treat peripheral diseases.

Quantum mechanical parameters-based study of aryl sulphonamides as 5-HT6 serotonin ligand using DFT methods

In the present work, quantum mechanical descriptors have been used for the development of quantitative structure activity relationship (QSAR) models for the thirty-two derivatives of aryl sulphonamide and sulfone based 5-HT6 antagonists. Among several classes of serotonin 5-HT6 receptor ligands, aryl sulphonamides reported better affinity towards the receptor. Drugs acting as serotonin ligands are useful in the treatment of a variety of mental disorders. The descriptors that have been used in our study are total energy, log P, molecular weight, dipole moment, heat of formation, LUMO energy, HOMO energy and electrophilicity index. The geometry optimization and evaluation of descriptors of all the compounds has been done with the help of CAChe Pro software using DFT-B88-LYP method with double-zeta valence polarized (DZVP) basis set. The best QSAR model for this set of derivatives has been obtained by combination of descriptors molecular weight, dipole moment and heat of formation. The descriptor molecular weight gives a mono-parametric QSAR model with remarkable predictive ability with positive contribution. The descriptor molecular weight is present in all best bi-parametric and tri-parametric QSAR models. Statistical parameters such as correlation coefficient, cross validation coefficient, standard error etc. were used to validate the predictability of QSAR models.

The 5-HT2A, 5-HT5A, and 5-HT6 serotonergic receptors in the medial prefrontal cortex behave differently in extinction learning: Does social support play a role?

Studies on the social modulation of fear have revealed that in social species, individuals in a distressed state show better recovery from aversive experiences when accompanied - referred to as social buffering. However, the underlying mechanisms remain unknown, hindering the understanding of such an approach. Our previous data showed that the presence of a conspecific during the extinction task inhibited the retrieval of fear memory without affecting the extinction memory in the retention test. Here, we investigate the role of serotonergic receptors (5-HTRs), specifically 5-HT2A, 5-HT5A, and 5-HT6 in the medial prefrontal cortex (mPFC), In the retention of extinction after the extinction task, in the absence or presence of social support. Extinction training was conducted on 60-day-old male Wistar rats either alone or with a conspecific (a familiar cagemate, non-fearful). The antagonists for these receptors were administered directly into the mPFC immediately after the extinction training. The results indicate that blocking 5-HT5A (SB-699551–10 μg/side) and 5-HT6 (SB-271046A - 10 μg/side) receptors in the mPFC impairs the consolidation of CFC in the social support group. Interestingly, blocking 5-HT2A receptors (R65777 - 4 μg/side) in the mPFC led to impaired CFC specifically in the group undergoing extinction training alone. These findings contribute to a better understanding of brain mechanisms and neuromodulation associated with social support during an extinction protocol. They are consistent with previously published research, suggesting that the extinction of contextual fear conditioning with social support involves distinct neuromodulatory processes compared to when extinction training is conducted alone.

Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex

Serotonin (5-HT) imbalances in the developing prefrontal cortex (PFC) are linked to long-term behavioral deficits. However, the synaptic mechanisms underlying 5-HT-mediated PFC development are unknown. We found that chemogenetic suppression and enhancement of 5-HT release in the PFC during the first two postnatal weeks decreased and increased the density and strength of excitatory spine synapses, respectively, on prefrontal layer 2/3 pyramidal neurons in mice. 5-HT release on single spines induced structural and functional long-term potentiation (LTP), requiring both 5-HT2A and 5-HT7 receptor signals, in a glutamatergic activity-independent manner. Notably, LTP-inducing 5-HT stimuli increased the long-term survival of newly formed spines ( ≥ 6 h) via 5-HT7 Gαs activation. Chronic treatment of mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first two weeks, but not the third week of postnatal development, increased the density and strength of excitatory synapses. The effect of fluoxetine on PFC synaptic alterations in vivo was abolished by 5-HT2A and 5-HT7 receptor antagonists. Our data describe a molecular basis of 5-HT-dependent excitatory synaptic plasticity at the level of single spines in the PFC during early postnatal development.

Mechanisms involved in the muscle relaxing effects of STW 5 in guinea pig stomach.

The herbal preparation STW 5 ameliorates functional dyspepsia partly by relaxing smooth muscle of the proximal stomach, thus improving gastric accommodation. We explored the unknown pathways responsible for this effect by testing targets known to modulate gastric smooth muscle relaxation. STW 5-induced relaxation of smooth muscle strips from guinea pig gastric corpus before and after pharmacological interventions were recorded with force transducers in an organ bath. ORAI1 mRNA expression was tested in the proximal stomach. Blockade of Ca2+-activated K+ and Cl- channels, voltage-gated L- or T-type Ca2+ channels, TRPA1-, TRPV1-, adenosine or 5-HT4 receptors, antagonizing ryanodine receptors, inhibiting cyclooxygenase or sarcoplasmic reticulum calcium ATPase did not affect STW 5-evoked relaxation. Likewise, protein-kinase A or G were not involved. However, the relaxation evoked by STW 5 was significantly reduced by phorbol-12-myristat-13-acetat, an activator of protein-kinase C, by 2- aminoethyldiphenylborinate, an inhibitor of the IP3 receptor-mediated Ca2+ release from the sarcoplasmic reticulum or by SKF-96365, a nonselective store-operated calcium entry (SOCE) blocker. Furthermore, the mixed TRPC3/SOCE inhibitor Pyr3, but not the selective TRPC3 blocker Pyr10, reduced the effect of STW 5. Finally, BTP2, a potent blocker of ORAI-coupled SOCE, almost abolished STW 5-evoked relaxation. Expression of ORAI1 could be demonstrated in the corpus/fundus. STW 5 inhibited SOCE, most likely ORAI channels, which are modulated by IP3- and PKC-dependent mechanisms. Our findings impact on the design of drugs to induce muscle relaxation and help identify phytochemicals with similar modes of actions to treat gastrointestinal disturbances.

THE EFFECTIVENESS OF GINGER (Zingiber officinale) AS AN ANTIEMETIC ON PREGNANT WOMEN

Nausea and vomiting during pregnancy are common occurrences in the first trimester. This can be attributed to an increase in estrogen and progesterone hormones produced by human chorionic gonadotropin (HCG) in the placenta. Various therapies can be employed as antiemetics in pregnant women, and one of them is traditional therapy involving the administration of ginger extract. This research design uses a literature review methodology, gathering data from international and national journals that meet the inclusion and exclusion criteria. The databases utilized include Google Scholar, PubMed, and Garuda. To understand the effectiveness of ginger extract administration as an antiemetic in pregnant women. The methodology employed is a literature review, utilizing the Google Scholar database to search for articles published between 2013 and 2023 in both Indonesian and English languages. Ginger can reduce nausea and vomiting by modulating gastrointestinal effects such as smooth muscle contractions and stimulating gastric motility. It inhibits 5-HT3 receptors in the central nervous system, hampers carminative effects, reduces cisplatin effects, and has effects similar to dimenhydrinate. Administering ginger infusion twice a day for 4-7 days has shown a decrease in the occurrence of nausea and vomiting in pregnant women. Additionally, ginger aromatherapy with 5 ml for four consecutive days can reduce the incidence of nausea and vomiting in pregnant women with hyperemesis gravidarum. Ginger extract can reduce nausea and vomiting in pregnant women.

Mechanisms underlying the laxative effect of lactulose: A randomized placebo-controlled trial showing increased small bowel water and motility unaltered by the 5-HT3 receptor antagonist, ondansetron.

Lactulose is a laxative which accelerates transit and softens stool. Our aim was to investigate its mechanism of action and use this model of diarrhea to investigate the anti-diarrheal actions of ondansetron. A double-blind, randomized, placebo-controlled crossover study of the effect of ondansetron 8 mg in 16 healthy volunteers. Serial MRI scans were performed fasted and 6 h after a meal. Participants then received lactulose 13.6 g twice daily and study drug for a further 36 h. On Day 3, they had further serial MRI scans for 4 h. Measurements included small bowel water content (SBWC), colonic volume, colonic gas, small bowel motility, whole gut transit, and ascending colon relaxation time (T1AC), a measure of colonic water content. Lactulose increased area under the curve (AUC) of SBWC from 0 to 240 min, mean difference 14.2 L · min (95% CI 4.1, 24.3), p = 0.009, and substantially increased small bowel motility after 4 h (mean (95% CI) 523 (457-646) a.u. to 852 (771-1178) a.u., p = 0.007). There were no changes in T1AC after 36 h treatment. Ondansetron did not significantly alter SBWC, small bowel motility, transit, colonic volumes, colonic gas nor T1AC, with or without lactulose. Lactulose increases SBWC and stimulates small bowel motility; however, unexpectedly it did not significantly alter colonic water content, suggesting its laxative effect is not osmotic but due to stimulation of motility. Ondansetron's lack of effect on intestinal water suggests its anti-diarrheal effect is not due to inhibition of secretion but more likely altered colonic motility.

Evolutionary conservation of putative suicidality-related risk genes that produce diminished motivation corrected by clozapine, lithium and antidepressants.

Genome wide association studies (GWAS) and candidate gene analyses have identified genetic variants and genes that may increase the risk for suicidal thoughts and behaviors (STBs). Important unresolved issues surround these tentative risk variants such as the characteristics of the associated genes and how they might elicit STBs. Putative suicidality-related risk genes (PSRGs) were identified by comprehensive literature search and were characterized with respect to evolutionary conservation, participation in gene interaction networks and associated phenotypes. Evolutionary conservation was established with database searches and BLASTP queries, whereas gene-gene interactions were ascertained with GeneMANIA. We then examined whether mutations in risk-gene counterparts in C. elegans produced a diminished motivation phenotype previously connected to suicide risk factors. From the analysis, 105 risk-gene candidates were identified and found to be: 1) highly conserved during evolution, 2) enriched for essential genes, 3) involved in significant gene-gene interactions, and 4) associated with psychiatric disorders, metabolic disturbances and asthma/allergy. Evaluation of 17 mutant strains with loss-of-function/deletion mutations in PSRG orthologs revealed that 11 mutants showed significant evidence of diminished motivation that manifested as immobility in a foraging assay. Immobility was corrected in some or all of the mutants with clozapine, lithium and tricyclic antidepressant drugs. In addition, 5-HT2 receptor and muscarinic receptor antagonists restored goal-directed behavior in most or all of the mutants. These studies increase confidence in the validity of the PSRGs and provide initial clues about possible mechanisms that mediate STBs.

Xiao Cheng Qi Decoction, an Ancient Chinese Herbal Mixture, Relieves Loperamide-Induced Slow-Transit Constipation in Mice: An Action Mediated by Gut Microbiota.

Xiao Cheng Qi (XCQ) decoction, an ancient Chinese herbal mixture, has been used in treating slow-transit constipation (STC) for years. The underlying action mechanism in relieving the clinical symptoms is unclear. Several lines of evidence point to a strong link between constipation and gut microbiota. Short-chain fatty acids (SCFAs) and microbial metabolites have been shown to affect 5-HT synthesis by activating the GPR43 receptor localized on intestinal enterochromaffin cells, since 5-HT receptors are known to influence colonic peristalsis. The objective of this study was to evaluate the efficacy of XCQ in alleviating clinical symptoms in a mouse model of STC induced by loperamide. The application of loperamide leads to a decrease in intestinal transport and fecal water, which is used to establish the animal model of STC. In addition, the relationship between constipation and gut microbiota was determined. The herbal materials, composed of Rhei Radix et Rhizoma (Rhizomes of Rheum palmatum L., Polygonaceae) 55.2 g, Magnoliae Officinalis Cortex (Barks of Magnolia officinalis Rehd. et Wils, Magnoliaceae) 27.6 g, and Aurantii Fructus Immaturus (Fruitlet of Citrus aurantium L., Rutaceae) 36.0 g, were extracted with water to prepare the XCQ decoction. The constipated mice were induced with loperamide (10 mg/kg/day), and then treated with an oral dose of XCQ herbal extract (2.0, 4.0, and 8.0 g/kg/day) two times a day. Mosapride was administered as a positive drug. In loperamide-induced STC mice, the therapeutic parameters of XCQ-treated mice were determined, i.e., (i) symptoms of constipation, composition of gut microbiota, and amount of short-chain fatty acids in feces; (ii) plasma level of 5-HT; and (iii) expressions of the GPR43 and 5-HT4 receptor in colon. XCQ ameliorated the constipation symptoms of loperamide-induced STC mice. In gut microbiota, the treatment of XCQ in STC mice increased the relative abundances of Lactobacillus, Prevotellaceae_UCG_001, Prevotellaceae_NK3B31_group, Muribaculaceae, and Roseburia in feces and decreased the relative abundances of Desulfovibrio, Tuzzerella, and Lachnospiraceae_ NK4A136_group. The levels of SCFAs in stools from the STC group were significantly lower than those the control group, and were greatly elevated via treatment with XCQ. Compared with the STC group, XCQ increased the plasma level of 5-HT and the colonic expressions of the GPR43 and 5-HT4 receptor, significantly. The underlying mechanism of XCQ in anti-constipation could be related to the modulation of gut microbiota, the increase in SCFAs, the increase in plasma 5-HT, and the colonic expressions of the GPR43 and 5-HT4 receptor. Our results indicate that XCQ is a potent natural product that could be a therapeutic strategy for constipation.

Synthesis and preclinical evaluation of [11C]uPSEM792 for PSAM4-GlyR based chemogenetics

Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM. PSAM4 is a triple mutant PSAM derived from the α7 nicotinic receptor (α7L131G,Q139L,Y217F). Although having no constitutive activity as a ligand-gated ion channel, PSAM4 has been coupled to the serotonin 5-HT3 receptor (5-HT3R) and to the glycine receptor (GlyR). Treatment with the partner PSEM to activate PSAM4-5-HT3 or PSAM4-GlyR, causes neuronal activation or silencing, respectively. A suitably designed radioligand may enable selective visualization of the expression and location of PSAMs with positron emission tomography (PET). Here, we evaluated uPSEM792, an ultrapotent PSEM for PSAM4-GlyR, as a possible lead for PET radioligand development. We labeled uPSEM792 with the positron-emitter, carbon-11 (t1/2 = 20.4 min), in high radiochemical yield by treating a protected precursor with [11C]iodomethane followed by base deprotection. PET experiments with [11C]uPSEM792 in rodents and in a monkey transduced with PSAM4-GlyR showed low peak radioactivity uptake in brain. This low uptake was probably due to high polarity of the radioligand, as evidenced by physicochemical measurements, and to the vulnerability of the radioligand to efflux transport at the blood–brain barrier. These findings can inform the design of a more effective PSAM4 based PET radioligand, based on the uPSEM792 chemotype.

Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents.

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders.

Effect of Bulky N-Dibenzofuranylmethyl Substitution on the 5-HT2 Receptor Affinity and Efficacy of a Psychedelic Phenethylamine.

The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype.

Structural diversity derivatization and studies on the nematicidal activity of tropane derivatives

Starting from the structure of MDL 72222 and its analogs, the known 5-HT3 receptor antagonists with verified nematicidal activity, we evaluated a diverse array of tropane derivatives that are characterized by the introduction of a variety of pentatomic heterocycles as bioisosteric replacements for the ester moiety of these 5-HT3 receptor antagonists. The in vitro nematicidal activities of all the target compounds were tested against Bursaphelenchus xylophilus and Meloidogyne incognita. A preliminary structure-activity relationship (SAR) investigation demonstrated that the ester functionality in 5-HT3 receptor antagonists could be replaced by a thiazole moiety (analog 5) with modest to good nematicidal activity. Specifically, compound 5bd exhibited excellent nematicidal activity against B. xylophilus with an LC50/72 h of 7.80 mg/L, and 85% mortality at 40 mg/L against M. incognita. Furthermore, a stepwise structural modification of analog 5 led to the discovery of the structurally distinct compound 47b with advanced nematicidal activity, which had an LC50/72 h of 5.96 mg/L against B. xylophilus.

In-silico Design, ADMET Screening, Prime MM-GBSA Binding Free Energy Calculation and MD Simulation of Some Novel Phenothiazines as 5HT6R Antagonists Targeting Alzheimer's Disease.

Alzheimer's disease is a type of dementia that affects neuronal function, leading to a decline in cognitive functions. Serotonin-6 (5HT6) receptors are implicated in the etiology of neurological diseases. 5HT6 receptor antagonists act as anti-dementia agents. 7YS6 represents a membrane protein, and amplification and overexpression of this protein are associated with Alzheimer's disease. Coumarin-fused phenothiazines are significant anti-Alzheimer's agents due to their inhibitory activity on the Serotonin- 6 receptor. Numerous previously unreported Coumarin-substituted Phenothiazines [A2 to A50] were designed using in-silico methods to evaluate their 5HT6 receptor antagonistic activity. Molecular modeling techniques were employed to study the ligands [A2 to A50] in interaction with the Serotonin-6 receptor (PDB ID: 7YS6) using Schrödinger Suite 2019-4. Molecular modeling studies of the designed ligands [A2 to A50] were conducted using the Glide module. In-silico ADMET screening was performed using the QikProp module, and binding free energy calculations were carried out using the Prime MM-GBSA module within the Schrödinger Suite. The binding affinity of the designed ligands [A2 to A50] towards 5HT6 receptors was determined based on Glide scores. Subsequently, ligand A31 underwent a 100 ns molecular dynamics simulation using the Desmond module of Schrödinger Suite 2020-1, which is based in New York, NY. The majority of the designed ligands exhibited strong hydrogen bonding interactions and hydrophobic associations with the serotonin-6 receptor, which hinder its activity. These ligands achieved remarkable Glide scores within the range of -4.2859 to -7.7128, in comparison to reference standards such as Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine (-5.54853), and the co-crystallized ligand (-7.02889). In-silico ADMET properties for these ligands fell within the recommended values for drug-likeness. It is worth noting that the MM-GBSA binding free energy of the most potent inhibitor was positive, indicating a strong binding interaction. Additionally, the dynamic behavior of the protein (7YS6)-ligand (A31) complex was studied by subjecting ligand A31 to a 100 ns molecular dynamics simulation. The results of this study reveal strong evidence supporting the potential of coumarin- substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands [A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti- Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm their therapeutic potential.

Phytomedicine Fructus Aurantii-derived two absorbed compounds unlock antidepressant and prokinetic multi-functions via modulating 5-HT3/GHSR

Ethnopharmacological relevanceFructus Aurantii (FA), a well-known phytomedicine, has been employed to evoke antidepressant and prokinetic multi-functions. Therein, systematically identifying bioactive components and the referred mechanism is essential for FA. Aim of the studyThis study was planned to answer “2 W” (What and Why), such as which components and pathways contribute to FA's multi-functions. We aimed to identify bioactive compounds as the key for opening the lock of FA's multi-functions, and the molecule mechanisms are their naturally matched lock cylinder. Materials and methodsThe phytochemical content of FA extract was determined, and the compounds were identified in rats pretreated with FA using liquid chromatography with mass spectrometry (LC-MS). The contribution strategy was used to assess bioactive compounds’ efficacy (doses = their content in FA) in model rats with the mechanism. The changes in functional brain regions were determined via 7.0 T functional magnetic resonance imaging-blood oxygen level-dependent (fMRI-BOLD). ResultEight phytochemicals’ content was detected, and merely six components were identified in rats in vivo. Meranzin hydrate + hesperidin (MH), as the primary contributor of FA, exerted antidepressant and prokinetic effects (improvement of indexes for immobility time, gastric emptying, intestinal transit, CRH, ghrelin, ACTH, DA, NA, 5-HT, CORT, and 5-HT3) by regulating 5-HT3/Growth hormone secretagogue receptor (GHSR) pathway. These results were validated by 5-HT2A, 5-HT3, and GHSR receptor antagonists combined with molecule docking. MH restored the excessive BOLD activation of the left accumbens nucleus, left corpus callosum and hypothalamus preoptic region. ConclusionAbsorbed MH accounts for FA's anti-depressant and prokinetic efficacy in acutely-stressed rats, primarily via 5-HT3/GHSR shared regulation.

Comparison of oral olanzapine versus oral ondansetron for prevention of postoperative nausea and vomiting in female patients undergoing laparoscopic cholecystectomy under general anaesthesia

Introduction: Postoperative nausea and vomiting is one of the significant problem in anaesthesia practice The incidence is even high following laparoscopic surgeries. 5HT3 receptor antagonists are routinely used to prevent postoperative nausea and vomiting (PONV). Olanzapine, an atypical antipsychotic drug with its activity on multiple receptor sites particularly at D2 and 5HT3 receptors, has potential antiemetic properties. This study aimed to compare the efficacy of ondansetron with olanzapine in prevention of PONV following laparoscopic cholesystectomy under general anaesthesia. Materials and methods: This randomized double blind controlled study was done by recruiting 120 female patients belonging to ASA I/II posted for laparoscopic cholecystectomy under general anaesthesia. Patients were assigned to one of the two groups. Group A received tablet Olanzapine 5mg, 4 hrs before surgery and Group B received tablet ondansetron 16mg 1hr before surgery. Postoperatively nausea, retching, vomiting complete response and sedation were assessed for 24hrs at the interval of 0-4hrs, 4-8hrs, 8-12hrs and 12-24hrs. Results: There was no statistical difference in the incidence of postoperative nausea, retching and vomiting between the groups at 0-4hrs, 4-8hrs. Statistical difference between the groups were seen at 8-12hr interval (nausea p=0.048, retching=0.042, vomiting p=0.042) and at 12-24 hr (nausea p=0.028, retching p=0.001, vomiting p=0.006). There was a significant difference in the use of rescue drug at 8-12hrs (6.7% patients required rescue drug in Group B whereas none required in Group B). Conclusion: Olanzapine 5 mg can be used safely and effectively for prophylaxis against PONV and is more effective in preventing PONV during the late postoperative period compared to ondansetron.