Serotonin 5-HT3 Receptor Research Articles

The Importance of Stereochemistry in 5-HT7R Modulation─A Case Study of Hydantoin Derivatives.

Serotonin 5-HT7 receptor (5-HT7R), one of the most recently discovered members of the serotonergic system, has become a promising target in the search for central nervous system disorders. Despite the number of preclinical results, none of the selective 5-HT7R agents has been approved; therefore, the clinical significance of this protein has not been confirmed yet. Recently, we described very promising, selective, and highly potent hydantoin-derived 5-HT7R antagonists with confirmed antidepressant activity in vivo and a very good ADMET profile; however, they have been tested in behavioral studies as racemates. In this work, the synthesis of optically pure hydantoin-derived 5-HT7R agents using cost-effective, classical methods has been presented for the first time. X-ray crystallographic analysis confirmed the absolute configuration on both stereogenic centers and allowed for the elucidation of the mechanism of introduction of epichlorohydrin into the hydantoin N3-position. The radioligand binding results showed a clear configuration preference for 5-HT7R affinity. The molecular modeling results further indicated the key interaction responsible for lower affinity (with amino acid I3 × 29). Finally, the comparison of the antidepressant and anxiolytic effects of racemates versus stereoisomers suggests an influence of additional, apart from the action on 5HT7R, factors responsible for the activity in vivo, which is worthy of deeper insight within further studies.

Experience of using Russian rizatriptan 10 mg tablets in routine clinical practice: results of a multicenter post-registration observational study “OPYT”

One of the key mediator systems involved in the pathogenesis of migraine is the serotonergic system, which led to the development and introduction of serotonin 5-HT1 receptor agonists (triptans) into clinical practice as the most important means of preventing migraine attacks. Serotonin 5-HT1 receptor agonists have a high selectivity for the 5-HT1B and 5-HT1D receptor subtypes, which ensures their effect on the pathogenesis of migraine attack development.Objective: to evaluate the efficacy of a standard dose of Relonova in the relief of four moderate to severe migraine attacks in outpatients in reallife clinical practice, including assessment of the rate of attack relief, the effect of the drug on headache intensity, concomitant symptoms and the general condition of the patient.Material and methods. The study involved 415 patients with migraine (319 women and 96 men; mean age 35.7±7.8 years). A total of 1660 migraine attacks were analyzed. The average number of migraine days per month was 6.72±3.99. Migraine attacks with aura were observed in 125 patients (30.1%). Patients stopped four migraine attacks and filled out self-monitoring diaries. Treatment efficacy was assessed according to the European Headache Federation (EHF) Consensus Algorithm for Determining Effective Treatment of a Migraine Attack.Results. After taking Relonova, pain became mild or disappeared completely in 30 minutes in 52% of patients, in 76% in 1 hour, in 93% in 2 hours, in 99% in 4 hours and in 99% of patients in 24 hours. A recurrence of the headache occurred in 8.8% of the attacks. Additional analgesic treatment after 30 minutes was required in 14% of cases, after which period the frequency did not exceed 2%. Adverse events were observed in 4% of patients and were mild. The overwhelming majority (90%) of study participants were able to successfully terminate three attacks and were responders.Conclusion. Relonova is an effective and safe agent to stop migraine attack and can be recommended for use in daily clinical practice.

Low-Basicity 5-HT6 Receptor Ligands from the Group of Cyclic Arylguanidine Derivatives and Their Antiproliferative Activity Evaluation

The serotonin 5-HT6 receptor (5-HT6R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT6R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT6R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT6R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug–drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio Rerio model. Two antagonists with an affinity constant Ki < 50 nM (PR 68 Ki = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug–drug interactions.

The interplay of serotonin 5-HT1A and 5-HT7 receptors in chronic stress.

Serotonin regulates multiple physiological and pathological processes in the brain, including mood and cognition. The serotonin receptors 5-HT1AR (also known as HTR1A) and 5-HT7R (also known as HTR7) have emerged as key players in stress-related disorders, particularly depression. These receptors can form heterodimers, which influence their functions. Here, we explored the developmental dynamics of 5-HT1AR and 5-HT7R expression and validated heterodimerization levels in the brain of control and stressed mice. In control animals, we found that there was an increase in 5-HT1AR expression over 5-HT7R in the prefrontal cortex (PFC) and hippocampus during development. Using a chronic unpredictable stress as a depression model, we found an increase in 5-HT7R expression exclusively in the PFC of resilient animals, whereas no changes in 5-HT1AR expression between control and anhedonic mice were obtained. Quantitative in situ analysis of heterodimerization revealed the PFC as the region exhibiting the highest abundance of 5-HT1AR-5-HT7R heterodimers. More importantly, upon chronic stress, the amount of heterodimers was significantly reduced only in PFC of anhedonic mice, whereas it was not affected in resilient animals. These results suggest an important role of brain-region-specific 5-HT1AR-5-HT7R heterodimerization for establishing depressive-like behaviour and for development of resiliency.

Precision defect integrated graphene as reliable support membrane for high-resolution cryo-transmission electron microscopy

Graphene is an excellent support film for high-resolution transmission electron microscopy (TEM) but its use with biological samples, notably in cryo-TEM, is hindered by its inherent hydrophobicity. Whereas surface treatments have been proposed to render graphene hydrophilic, they are often difficult to reproduce due to a lack of information on the structural changes that modify the wetting properties of graphene. This study aims to correlate the atomic structure of graphene with its wetting properties to allow a reproducible protocol to advance its application in cryo-TEM. We follow the change in the atomic structure of graphene as a function of low-energy hydrogen plasma treatment duration on monolayer graphene transferred onto TEM grids. With finely controlled plasma exposure, partial hydrogenation, monoatomic vacancies, and pores of a few nanometers are realized in the graphene. The introduction of defects (vacancies and pores) enables the formation of continuous layers of vitreous ice on TEM grids. Grids with defect-integrated graphene are reproduced and used in the vitrification of the mouse serotonin 5-HT3 receptor, a membrane protein. Single particle analysis of the membrane protein on graphene compared to conventional holey carbon film give insight into the strengths and discretions in using graphene membrane for protein structural studies.

Development and characterization of transdermal drug delivery system of ramosetron HCL using different polymers and their effect on In-vitro release

Transdermal Drug Delivery Systems (TDDS) offer a controlled and consistent release of medications, bypassing first-pass metabolism and minimizing side effects associated with traditional oral and intravenous therapies. This study focuses on the development and evaluation of Ramosetron HCl transdermal patches designed for sustained release to manage nausea and vomiting. Ramosetron HCl, a selective 5-HT₃ serotonin receptor antagonist, was incorporated into various formulations using different grades of Hydroxypropyl Methylcellulose (HPMC), Polyvinyl Pyrrolidone (PVP K30), and Polysorbate 80. The patches were prepared by solvent casting and evaluated for various parameters including thickness, weight variation, drug content, folding endurance, tensile strength, and in-vitro drug release. The calibration curve for Ramosetron HCl in 7.4 pH phosphate buffer was established with a λmax of 240 nm. Fourier Transform Infrared Spectroscopy (FTIR) was employed to ensure compatibility between the drug and excipients. Formulation F5 demonstrated optimal properties, including satisfactory drug release profiles and mechanical strength. Stability studies of F5 showed that the formulation maintained its release characteristics under accelerated storage conditions (40°C / 75% RH) for up to three months. This study confirms the potential of Ramosetron HCl transdermal patches as an effective alternative to oral dosage forms, providing sustained drug delivery and enhanced patient compliance.

Effects of a 5-HT4 receptor antagonist in the caudate nucleus on the performance of macaques in a delayed reward task

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT4 receptor (5-HT4R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT4R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT4R in the dCDh. We then examined the effects of a specific 5-HT4R antagonist infused into the dCDh. Blockade of 5-HT4R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT4R blockade because saline controls showed no such effect. The results demonstrate that 5-HT4Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT4R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms.

Analytical Methods for Tetracyclic Antidepressants: A Comprehensive Review

ABSTRACTDepression is a mental illness that affects patients’ behavior, and it impacts approximately 264 million people globally. Tetracyclic antidepressants (TeCAs) are one class of medication that is available for the treatment of depression. These medications work by modifying hormones such as serotonin, norepinephrine, and dopamine. TeCAs, such as setiptiline, amoxapine, mianserin, maprotiline, and mirtazapine, are four ring‐based compounds that assist in preventing the brain from reabsorbing the neurotransmitters norepinephrine and serotonin. Each of these medications interacts with adrenergic (α1 and α2) and serotonin (5HT1 and 5HT2) receptors independently. Using biological samples (plasma, blood, and urine) and pharmaceutical formulations, this review focuses on providing a complete overview of the various analytical conditions maintained for the medications in the above class and their metabolites. Major analytical methods such as mass spectrometry, gas chromatography, and high‐performance liquid chromatography are used to quantify and determine the drugs. This review provides a thorough understanding of impurity identification, pharmacokinetic and stability evaluations, and structural degradation quantification. It provides valuable and reliable information for research, enhancing their understanding of the subject matter.

Role of calcitonin gene-related peptide (CGRP) receptor antagonist in acute and preventive treatment of migraine.

Migraine is the most common neurological disease in the world. It is characterized by recurrent attacks of severe headaches of a one-sided, throbbing nature, often accompanied by sensory and motor disturbances and generally associated with nausea and increased sensitivity to light and sound. Migraine treatment can be divided into emergency treatment and preventive treatment, which aims to reduce the overall frequency and severity of attacks. In the first case, nonsteroidal anti-inflammatory drugs (NSAIDs) can be used, but in some patients they do not have the desired effect. The gold standard in the fight against migraine pain are triptans (selective serotonin 5-HT1 receptor agonists), although they too are not effective in all patients. Current understanding suggests that CGRP plays a significant role in the pathophysiology of migraines. Evidence supporting this includes increased CGRP levels during migraine attacks, causing inflammation and activation of other pathophysiological processes responsible for pain. The hope for patients are CGRP receptor antagonists, which greatly expand therapeutic options.

Serotonin and vasovagal syncope.

The goal of this manuscript was to review the biological and clinical evidence that serotonin neurotransmission might play an important role in the physiology and treatment of vasovagal syncope. The authors reviewed PubMed and handsearches of secondary sources for papers related to the Bezold-Jarisch reflex and serotonin, the plausible involvement of the Bezold-Jarisch reflex in vasovagal syncope, and three lines of clinical evidence involving serotonin and the syncope. The Bezold-Jarisch reflex was first described following the infusion of veratrum alkaloids into animals in the 19th century. The reflex is triggered by serotonin stimulation chemoreceptors and mechanoreceptors in the the left ventricle. The afferent component of the reflex is carried by unmyelinated type C vagal nerve fibers, which results in parasympathetic efferent stimulation that causes bradycardia. The similarity of the combination of hypotension and bradycardia in the Bezold-Jarisch reflex and in vasovagal syncope led to the suggestion that the reflex was the cause of the syndrome. Three lines of evidence implicate the serotonin 5HT3 receptors in the heart in the reflex. There is genetic and physiologic evidence for the serotonin 5HT1A and 5HT3 receptors and the serotonin reuptake transporter (SERT). Acute blockade of SERT induces vasovagal syncope in humans undergoing head-up tilt table testing, and SERT inhibition reduces hypotension and bradycardia during spinal anaesthesia. Finally, three randomized clinical trials of SERT inhibitors uniformly reported that they significantly reduce the likelihood of vasovagal syncope recurrences. Multiple lines of evidence implicate serotonin neurotransmission in the cause of vasovagal syncope.

Effect of amisulpride on the expression of serotonin receptors, neurotrophic factor BDNF and its receptors in mice with overexpression of the aggregation-prone [R406W] mutant tau protein.

Serotonin 5-HT7 receptors (5-HT7R) are attracting increasing attention as important participants in the mechanisms of Alzheimer's disease and as a possible target for the treatment of various tau pathologies. In this study, we investigated the effects of amisulpride (5-HT7R inverse agonist) in C57BL/6J mice with experimentally induced expression of the gene encoding the aggregation-prone human Tau[R406W] protein in the prefrontal cortex. In these animals we examined short-term memory and the expression of genes involved in the development of tauopathy (Htr7 and Cdk5), as well as biomarkers of neurodegenerative processes - the Bdnf gene and its receptors TrkB (the Ntrk2 gene) and p75NTR (the Ngfr gene). In a short-term memory test, there was no difference in the discrimination index between mice treated with AAV-Tau[R406W] and mice treated with AAV-EGFP. Amisulpride did not affect this parameter. Administration of AAV-Tau[R406W] resulted in increased expression of the Htr7, Htr1a, and Cdk5 genes in the prefrontal cortex compared to AAV-EGFP animals. At the same time, amisulpride at the dose of 10 mg/kg in animals from the AAV-Tau[R406W] group caused a decrease in the Htr7, Htr1a genes mRNA levels compared to animals from the AAV-Tau[R406W] group treated with saline. A decrease in the expression of the Bdnf and Ntrk2 genes in the prefrontal cortex was revealed after administration of AAV-Tau[R406W]. Moreover, amisulpride at various doses (3 and 10 mg/kg) caused the same decrease in the transcription of these genes in mice without tauopathy. It is also interesting that in mice of the AAV-EGFP group, administration of amisulpride at the dose of 10 mg/kg increased the Ngfr gene mRNA level. The data obtained allow us to propose the use of amisulpride in restoring normal tau protein function. However, it should be noted that prolonged administration may result in adverse effects such as an increase in Ngfr expression and a decrease in Bdnf and Ntrk2 expression, which is probably indicative of an increase in neurodegenerative processes.

Neutrophil-Lymphocyte Ratio Values in Schizophrenia: A Comparison between Oral and Long-Acting Antipsychotic Therapies.

Schizophrenia is a mental disorder affecting approximately 0.32% of the global population, according to the World Health Organization. Antipsychotic medications are used to treat this condition by inhibiting D2 dopamine and 5HT2 serotonin receptors. The selection of the appropriate mode of delivery for these drugs is based on factors such as patient adherence, clinical presentation, and patient preferences. However, additional drivers of treatment selection are required in clinical practice. Mounting evidence suggests that neuroinflammation plays a crucial role in the pathogenesis of schizophrenia. NLR, a cost-effective biomarker of inflammation, has increased in several psychiatric conditions and may represent a valid method for studying the inflammatory stage in schizophrenia, relapse, and the first episode of psychosis. The aim of this study is to evaluate whether there are any variations in NLR values between patients given oral antipsychotics and those given long-acting antipsychotics. The study included 50 individuals with schizophrenia, either acute or in the follow-up phase. NLR was obtained by calculating the ratio of absolute neutrophil count (cells/μL) and absolute lymphocyte count (cells/μL). Patients on long-acting antipsychotics exhibited significantly lower mean NLR scores (1.5 ± 0.7) compared to those on oral antipsychotics (2.2 ± 1.3) (p < 0.05). NLR appears promising as a neuroinflammatory biomarker. This study reveals significantly lower NLR values in patients on long-acting antipsychotics, which may signify reduced systemic inflammation and improved adherence.

Recent Advances in the Treatment of Irritable Bowel Syndrome: Addressing Diarrhea, Constipation, and Abdominal Pain

Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder characterized by abdominal pain, bloating, and changes in bowel habits. This paper aim was to provide an overview of recent advancements in the treatment of IBS, focusing on the management of its main symptoms: diarrhea, constipation, and abdominal pain. For individuals with IBS-D, various therapeutic options are available, including rifaximin, peripheral opioid agonists, mixed opioid agonists/antagonists, bile acid sequestrants, and serotonin 5-HT3 receptor antagonists. Rifaximin, a nonabsorbable antibiotic, has demonstrated significant effectiveness in reducing IBS symptoms, such as bloating and loose stools, with good tolerability and safety. Also the repeated use of rifaximin for managing recurrent IBS symptoms. In IBS-C patients, bulking agents, osmotic laxatives, and prokinetic agents like lubiprostone have shown efficacy in improving constipation and overall symptoms. Linaclotide, a drug that increases intestinal chloride secretion, has demonstrated significant improvement in bowel movements and abdominal pain in IBS-C patients. However, it may cause diarrhea in some individuals. IBS-M, characterized by alternating constipation and diarrhea, poses a challenge in terms of specific drug treatments. A comprehensive assessment of potential underlying causes and careful history taking is crucial for effective management. Abdominal pain is a common symptom in IBS, regardless of subtype. Antispasmodic drugs, peppermint oil, and trimebutine have shown effectiveness in reducing pain and improving symptoms. Antidepressants, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may offer relief by modulating pain pathways and influencing gastrointestinal motility. Benzodiazepines, particularly dextofisopam, have shown potential in improving stool consistency but require further evaluation. In conclusion, recent advancements in the treatment of IBS have provided a range of therapeutic options targeting its main symptoms. However, further research is needed to develop tailored treatments for specific IBS subtypes and to explore the efficacy of potential alternatives, including benzodiazepines. Improved management of IBS symptoms can significantly enhance the quality of life for affected individuals.

Phytoconstituents Targeting the Serotonin 5-HT3 Receptor: Promising Therapeutic Strategies for Neurological Disorders.

The 5-hydroxytryptamine-3 receptor (5-HT3R), a subtype of serotonin receptor, is a ligand-gated ion channel crucial in mediating fast synaptic transmission in the central and peripheral nervous systems. This receptor significantly influences various neurological activities, encompassing neurotransmission, mood regulation, and cognitive processing; hence, it may serve as an innovative target for neurological disorders. Multiple studies have revealed promising results regarding the beneficial effects of these phytoconstituents and extracts on conditions such as nausea, vomiting, neuropathic pain depression, anxiety, Alzheimer's disease, cognition, epilepsy, sleep, and dyskinesia via modulation of 5-HT3R in the pathophysiology of neurological disorder. The review delves into a detailed exploration of in silico, in vitro, and in vivo studies and clinical studies that discussed phytoconstituents acting on 5-HT3R and attenuates difficulties in neurological diseases. The diverse mechanisms by which plant-derived phytoconstituents influence 5-HT3R activity offer exciting avenues for developing innovative therapeutic interventions. Besides producing an agonistic or antagonistic effect, some phytoconstituents exert modulatory effects on 5-HT3R activity through multifaceted mechanisms. These include γ-aminobutyric acid and cholinergic neuronal pathways, interactions with neurokinin (NK)-1, NK2, serotonergic, and γ-aminobutyric acid(GABA)ergic systems, dopaminergic influences, and mediation of calcium ions release and inflammatory cascades. Notably, the phytoconstituent's capacity to reduce oxidative stress has also emerged as a significant factor contributing to their modulatory role. Despite the promising implications, there is currently a dearth of exploration needed to understand the effect of phytochemicals on the 5-HT3R. Comprehensive preclinical and clinical research is of the utmost importance to broaden our knowledge of the potential therapeutic benefits associated with these substances.

Effect of White Rice Flour in the Formulation Development and Evaluation of Sumatriptan Succinate Floating Microspheres by Modified Emulsion Solvent Diffusion Method

A sustained release system for Sumatriptan designed to increase its residence time in the stomach without contact with the Microspheres was achieved through the preparation of floating Microspheres by the Modified Emulsion solvent Diffusion method. In the present study attempt has been made to develop sustained released drug delivery system by formulating the floating Microspheres of Sumatriptan using White Rice Flour powder as a natural polymer which is biodegradable, biocompatible, nontoxic, economically cheap cost, devoid of adverse and side effects and easily availability. Sumatriptan Succinate is the succinate salt form of sumatriptan, a member of the triptan class of compounds with anti-migraine property. Sumatriptan succinate selectively binds to and activates serotonin 5-HT1 receptors. The 12 batches of floating Microspheres (MF1 to MF12) were formulated by Modified Emulsion solvent Diffusion method using different ratio of polymers like White Rice Flour power, HPMC K4M and Carbopol. The formulated Microspheres were evaluated by means of different parameters like shape and density of Microsphere, drug content uniformity, In-vitro buoyancy, swelling Index, In-vitro dissolution studies. The formulation MF6 has better sustained release when compared other formulations, hence we conclude that the combination of White Rice Flour powder, HPMC K4M shows better Gastric retention time which sustains the release of the dosage form.

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review.

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI, or DOX where X = -I) was first synthesized in 1973 in a structure-activity study to explore the effect of various aryl substituents on the then newly identified, and subsequently controlled, hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, or DOX where X = -CH3). Over time, DOI was found to be a serotonin (5-HT) receptor agonist using various peripheral 5-HT receptor tissue assays and later, following the identification of multiple families of central 5-HT receptors, an agonist at 5-HT2 serotonin receptors in rat and, then, human brain. Today, classical hallucinogens, currently referred to as serotonergic psychedelic agents, are receiving considerable attention for their potential therapeutic application in various neuropsychiatric disorders including treatment-resistant depression. Here, we review, for the first time, the historical and current developments that led to DOI becoming a unique, perhaps a landmark, agent in 5-HT2 receptor research.

Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT3 receptors.

Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT3 receptor (5-HT3R), which features two properties: VTX acts differently on rodent and human 5-HT3R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist-bound-like state of human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.

Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist.

Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.

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.

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.