Class Of Receptor Antagonists Research Articles

Comprehensive analysis of nizatidine: Pharmacodynamics and pharmacokinetics in anti-ulcer treatment

Ulcers are characterized histologically as lesions that penetrate through the muscularis mucosae into the submucosal layer, affecting any segment of the gastrointestinal (GI) tract mucosa. They often arise due to excessive acid production from peptic secretions. Nizatidine (NZT) is a potent H2-receptor antagonist used to reduce basal, nocturnal, and stimulated gastric acid secretion. This medication is commonly prescribed for conditions such as gastroesophageal reflux disease, peptic ulcers, and duodenal ulcers. As a member of the histamine H2 receptor antagonist class introduced before proton pump inhibitors, Nizatidine is noted for its effectiveness comparable to ranitidine. However, Nizatidine is distinguished by its thiazole ring, in contrast to the furan ring found in ranitidine. When administered orally, Nizatidine, especially in combination with antacids, enhances drug delivery to parietal cell receptors, improving the overall bioavailability of the medication and its ability to suppress acid secretion. Nizatidine is primarily absorbed in the proximal small intestine, exhibiting about 70% absolute bioavailability. Its lower absorption from the colon and a short biological half-life (ranging from 1 to 1.6 hours) suggest the potential benefits of developing sustained-release formulations such as floating gels to prolong its therapeutic effects. Clinical studies indicate that Nizatidine, in doses of 300 mg at bedtime or 150 mg twice daily, shows superior efficacy compared to other H2-receptor antagonists for managing duodenal and gastric ulcers as well as gastroesophageal reflux disease.

Electrochemical Oxidation of Ranitidine using a Boron-Doped Diamond Electrode in the Presence of Anionic Surfactant: A Comprehensive Investigation

Ranitidine (RAN) is a drug from the histamine H2 receptor antagonist class and is used to prevent excessive production of stomach acid. An electrochemical investigation of the RAN in pharmaceutical preparation and spiked human urine was performed for the using a boron-doped diamond electrode (BDDE). Voltammetric measurements were performed in a pH 11 BR solution supplemented with the anionic surfactant, sodium dodecyl sulfate (SDS). In the proposed method using optimized experimental conditions, linearity was obtained for RAN in the concentration range of 0.8-50.0 μM. The LOD value obtained is 0.22 μM. Good selectivity, accuracy, precision, and acceptable repeatability were also achieved in this proposed electrochemical sensor. Finally, this electrochemical sensor was successfully used for RAN detection in pharmaceutical samples.

Preparation and preliminary evaluation of a tritium-labeled allosteric P2X4 receptor antagonist

P2X4 receptors are ATP-gated cation channels that were proposed as novel drug targets due to their role in inflammation and neuropathic pain. Only few potent and selective P2X4 receptor antagonists have been described to date. Labeled tool compounds suitable for P2X4 receptor binding studies are lacking. Here, we present a novel allosteric P2X4 receptor antagonist possessing high potency in the low nanomolar range. We describe its tritium-labeling resulting in the P2X4-selective radiotracer [3H]PSB-OR-2020 with high specific activity (45 Ci/mmol; 1.67 TBq/mmol). A radioligand binding assay was developed using human embryonic kidney (HEK293) cell membranes recombinantly expressing the human P2X4 receptor. Competition binding studies with structurally diverse P2X4 receptor antagonists revealed different allosteric binding sites indicating that the new class of P2X4 receptor antagonists, to which PSB-OR-2020 belongs, interacts with an unprecedented allosteric site. [3H]PSB-OR-2020 may become a useful tool for research on P2X4 receptors and for promoting drug development.

IN SILICO STUDIES OF SOME NEWLY DESIGNED BENZIMIDAZOLETHIAZOLIDINONE BASED ANTAGONISTS OF HUMAN ESTROGEN RECEPTOR

Breast cancer is globally associated with majority of the women. Indeed, high estrogen levels are the most common subtype of breast cancer. Three different classes of estrogen receptor antagonists are frequently used to treat such kinds of breast cancers. Each of these interacts directly with the initiation and activation of the estrogen signalling pathway. However, new medicines must be developed because resistance limits the therapeutic effectiveness. In silico studies for drug discovery have become popular in recent years due to their low cost and quick execution. To develop novel therapeutics for breast cancer, three different series of benzimidazole compounds targeting the estrogen receptor were docked. Among these three series, benzimidazole fused with pyrazole showed significant results and the leading compound was 32 based on docking results. The docking data was further validated by executing molecular dynamics (MD) simulations for the stability of designed leads within the macromolecular cavity in relation to time. Therefore, it is proposed that the pyrazole fused benzimidazole nucleus can be a promising pharmacophore for developing novel anticancer therapeutics for breast cancer.

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives.

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

Calcitonin receptors in GtoPdb v.2023.1

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [131, 74, 71]) are generated by the genes CALCR (which codes for the CT receptor, CTR) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of AMY receptors [131], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [93]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the "gepant" class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [58, 15]. The summary table only reflects human receptor pharmacology.

Ocedurenone: A Novel Therapy for Uncontrolled Hypertension in Advanced Chronic Kidney Disease

Patients with advanced-stage chronic kidney disease (CKD) have a high burden of disease, which is compounded by serious comorbidities, including diabetes, cardiovascular disease (CVD), and, most commonly, hypertension. Control of hypertension is vital in patients with advanced CKD to reduce the associated risks of morbidity and mortality, but treatment options are limited, largely due to safety concerns for the use of existing antihypertensive agents in patients with poor renal function. During interviews conducted by EMJ in November 2022, two leading specialists in nephrology and cardiology, George Bakris, American Heart Association Comprehensive Hypertension Center, Department of Medicine, The University of Chicago Medicine, Illinois, USA, and Faiez Zannad, Clinical Investigation Centre (CIC 1493 Inserm-CHU), Université de Lorraine, Nancy, France; and Regional and University Hospital Center (CHRU) Nancy, France, discussed the challenges of treating uncontrolled hypertension in advanced CKD. These two experts described the complicated relationship between cardiovascular and renal disease, and identified significant unmet needs for patients with uncontrolled hypertension and advanced CKD. In this context, new agents in the field were viewed with interest, including the emerging class of non-steroidal mineralocorticoid receptor antagonists (MRA). The experts highlighted data from recent studies on the novel non-steroidal MRA, ocedurenone (KBP-5074), and discussed its potential as a treatment for uncontrolled hypertension in patients with advanced CKD.

Long-Term Use of Insomnia Medications: An Appraisal of the Current Clinical and Scientific Evidence.

While evidence supports the benefits of medications for the treatment of chronic insomnia, there is ongoing debate regarding their appropriate duration of use. A panel of sleep experts conducted a clinical appraisal regarding the use of insomnia medications, as it relates to the evidence supporting the focus statement, "No insomnia medication should be used on a daily basis for durations longer than 3 weeks at a time". The panelists' assessment was also compared to findings from a national survey of practicing physicians, psychiatrists, and sleep specialists. Survey respondents revealed a wide range of opinions regarding the appropriateness of using the US Food and Drug Administration (FDA)-approved medications for the treatment of insomnia lasting more than 3 weeks. After discussion of the literature, the panel unanimously agreed that some classes of insomnia medications, such as non-benzodiazepines hypnotics, have been shown to be effective and safe for long-term use in the appropriate clinical setting. For eszopiclone, doxepin, ramelteon and the newer class of dual orexin receptor antagonists, the FDA label does not specify that their use should be of a limited duration. Thus, an evaluation of evidence supporting the long-term safety and efficacy of newer non-benzodiazepine hypnotics is timely and should be considered in practice recommendations for the duration of pharmacologic treatment of chronic insomnia.

Synthesis, Characterization, and Biological Evaluation of 2-(N-((2′-(2H-tetrazole-5-yl)-[1,1′-biphenyl]-4yl)-methyl)-pentanamido)-3-methyl Butanoic Acid Derivatives

This study aimed to evaluate 2-(N-((2'-(2H-tetrazole-5-yl)-[1,1'-biphenyl]-4yl)-methyl)-pentanamido)-3-methyl butanoic acid-based ester derivatives as a new class of angiotensin-II receptor antagonists. For this purpose, a series of compounds were synthesized using a variety of phenols. Their chemical characterization was established by FTIR, 1HNMR, and 13CNMR techniques. The biological activities including antioxidant potentials using the DPPH assay, the antihypertensive assay, the urease enzyme inhibition assay, and the antibacterial assay using agar well diffusion methods were performed. All the new compounds showed significant free radical scavenging potentials more than the parent drug while retaining antihypertensive potentials along with urease inhibition properties. However, the AV2 test compound was found to be the most potent against hypertension. Most of the synthesized analogs showed urease inhibitory actions. Molecular docking studies were performed for all the active analogs to decode the binding detail of the ligands with receptors of the enzyme's active site.

Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists.

Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.

Daridorexant: A New Dual Orexin Receptor Antagonist for Insomnia.

Objective: To review the safety, efficacy, and tolerability of daridorexant in treating insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adult patients. Data Sources: A literature search was performed through PubMed using the following key terms: daridorexant, ACT-541468, orexin, insomnia, and sleep. Study Selection and Data Extraction: Selected articles included those which described clinical studies of the pharmacokinetics, efficacy, safety, or tolerability of daridorexant. Data Synthesis: Daridorexant works through antagonism of the dual orexin receptor. It is the third agent in this class of medications approved by the U.S. Food and Drug Administration (FDA). Daridorexant, at a dose of 25 mg to 50 mg, was shown to be effective in improving sleep parameters in phase 3 clinical studies and was well tolerated. Adverse event rates from phase 2 and 3 clinical trials were low with fatigue, nasopharyngitis, gait disturbance, somnolence, diarrhea, and headache most commonly reported. Conclusions: All currently available agents for treating insomnia have received a "weak" recommendation in the clinical practice guidelines, including the dual orexin receptor antagonist class of medications. Initial data suggest that with routine use daridorexant does not impair next day functioning, a common issue with other agents used to treat insomnia. In addition, daridorexant appears to be as safe and effective in treating insomnia in patients of all ages including those ≥65 years of age.

Positive interaction between GPER and β-alanine in the dorsal root ganglion uncovers potential mechanisms: mediating continuous neuronal sensitization and neuroinflammation responses in neuropathic pain

BackgroundThe pathogenesis of neuropathic pain and the reasons for the prolonged unhealing remain unknown. Increasing evidence suggests that sex oestrogen differences play a role in pain sensitivity, but few studies have focused on the oestrogen receptor which may be an important molecular component contributing to peripheral pain transduction. We aimed to investigate the impact of oestrogen receptors on the nociceptive neuronal response in the dorsal root ganglion (DRG) and spinal dorsal horn using a spared nerve injury (SNI) rat model of chronic pain.MethodsWe intrathecally (i.t.) administered a class of oestrogen receptor antagonists and agonists intrathecal (i.t.) administrated to male rats with SNI or normal rats to identify the main receptor. Moreover, we assessed genes identified through genomic metabolic analysis to determine the key metabolism point and elucidate potential mechanisms mediating continuous neuronal sensitization and neuroinflammatory responses in neuropathic pain. The excitability of DRG neurons was detected using the patch-clamp technique. Primary culture was used to extract microglia and DRG neurons, and siRNA transfection was used to silence receptor protein expression. Immunofluorescence, Western blotting, RT-PCR and behavioural testing were used to assess the expression, cellular distribution, and actions of the main receptor and its related signalling molecules.ResultsIncreasing the expression and function of G protein-coupled oestrogen receptor (GPER), but not oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ), in the DRG neuron and microglia, but not the dorsal spinal cord, contributed to SNI-induced neuronal sensitization. Inhibiting GPER expression in the DRG alleviated SNI-induced pain behaviours and neuroinflammation by simultaneously downregulating iNOS, IL-1β and IL-6 expression and restoring GABAα2 expression. Additionally, the positive interaction between GPER and β-alanine and subsequent β-alanine accumulation enhances pain sensation and promotes chronic pain development.ConclusionGPER activation in the DRG induces a positive association between β-alanine with iNOS, IL-1β and IL-6 expression and represses GABAα2 involved in post-SNI neuropathic pain development. Blocking GPER and eliminating β-alanine in the DRG neurons and microglia may prevent neuropathic pain development.

Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model.

In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca2+-permeable, and are responsible for mediating abnormal Ca2+ influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor-mediated, abnormal Ca2+ influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.

Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists

The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists’ potency from pIC50 values of 5.7–7.6, ADME properties (logD7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.

Calcitonin receptors in GtoPdb v.2021.2

This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [131, 74, 71]) are generated by the genes CALCR (which codes for the CT receptor) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [131], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin, α-CGRP (formerly known as CGRP-I), β-CGRP (formerly known as CGRP-II), amylin (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin and adrenomedullin 2/intermedin. There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CT receptor but it is not expressed in humans [94]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide, erenumab, and the "gepant" class of CGRP receptor antagonists.

CGRP receptor antagonists for migraine. Are they also AMY1 receptor antagonists?

The development of several drugs that target the calcitonin gene-related peptide (CGRP) system has been a major breakthrough in the pharmacological management of migraine. These are divided into two major classes, antibodies which bind to the CGRP peptide, preventing it from activating CGRP receptors and receptor antagonists. Within the receptor antagonist class, there are two mechanisms of action, small molecule receptor antagonists and an antibody antagonist. This mini-review considers the pharmacology of these receptor targeted antagonist drugs at the CGRP receptor and closely related AMY1 receptor, at which CGRP may also act. The antagonists are most potent at the CGRP receptor but can also show antagonism of the AMY1 receptor. However, important data are missing and selectivity parameters cannot be provided for all antagonists. The clinical implications of AMY1 receptor antagonism are unknown, but we urge consideration of this receptor as a potential contributing factor to CGRP and antagonist drug actions. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Preventive Migraine Treatment.

This article provides an overview of preventive interventions for migraine, including when to start and how to choose a treatment, pharmacologic options (both older oral treatments and new monoclonal antibodies to calcitonin gene-related peptide [CGRP] or its receptor), nonpharmacologic treatment such as neuromodulation, and preventive treatment of refractory migraine. The migraine preventive treatment landscape has been transformed by the development of monoclonal antibodies targeting CGRP or its receptor. These treatments, which are given subcutaneously or intravenously monthly or quarterly, have high efficacy and were well tolerated in clinical trials. Emerging real-world studies have found higher rates of adverse events than were seen in clinical trials. They are currently recommended for use if two traditional preventive therapies have proven inadequate. Since the commonly cited 2012 American Headache Society/American Academy of Neurology migraine prevention guidelines were released, clinical trials supporting the preventive use of lisinopril, candesartan, and memantine have been published. Neuromodulation devices, including external trigeminal nerve stimulation and single-pulse transcranial magnetic stimulation devices, have modest evidence to support preventive use. The American Headache Society/American Academy of Neurology guidelines for the preventive treatment of migraine are currently being updated. A new class of oral CGRP receptor antagonists (gepants) is being tested for migraine prevention. Successful preventive treatment of migraine reduces disease burden and improves quality of life. Many pharmacologic and nonpharmacologic treatment options are available for the prevention of migraine, including newer therapies aimed at the CGRP pathway as well as older treatments with good evidence for efficacy. Multiple treatment trials may be required to find the best preventive for an individual patient.

Deciphering the molecular basis of the kappa opioid receptor selectivity: A Molecular Dynamics study

Selective antagonists for the kappa opioid receptor (KOP) have the potential to treat opiate and alcohol addiction, as well as depression and other CNS disorders. Over the years, the development of KOP-selective antagonists yielded very few successful compounds. Recently, N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have emerged as a novel class of pure opioid receptor antagonists, including the marketed Mu opioid receptor (MOP) peripheral antagonist Alvimopan and the potent KOP antagonist JDTic. However, the selectivity determinants of this class of compounds towards the opioid receptor subtypes are still vague and understudied. In this work, we have performed Molecular Dynamics (MD) simulation to gain insights into the differential binding of this class of compounds into KOP, as exemplified by Alvimopan and JDTic. Our study indicated that the selectivity largely depends on ligands interaction with the selectivity pocket formed by Val108, Thr111, and Val118, supported by two additional polar and hydrophobic contacts with Asp138 and Trp287, respectively. Our results also demonstrate, for the first time, that non-morphinan ligands can still adopt the “message-address model” for KOP efficacy and selectivity by binding to Glu297.

Fast-dissolving Sublingual Nanofibers of Ondansetron Hydrochloride: Formulation, Physicochemical Characterization, and Clinical Evaluation on Post-cataract Surgery Patients

Objective: Ondansetron hydrochloride (OND) is an antiemetic agent belongs to the 5-HT3 receptor antagonist class administrated widely in relieving nausea and vomiting which is the most common complication occurred after surgery. This study aimed to design and evaluate the physicochemical along with clinical effects of fast-dissolving nanofiber (FDN) of OND administrated sublingually to enhance the bioavailability, effectiveness, and patient compliance compared to orally disintegrating tablets (ODT). Methods: Nanofibers were prepared by the electrospinning method, using polyvinyl alcohol and alpha-cyclodextrin as polymers and sodium saccharin as the sweetener. Physicochemical and mechanical characteristics of nanofibers were examined then the clinical evaluation was performed. Eighty patients volunteering for cataract surgery were randomly divided into two groups, one received FDN, and the other treated with ODT of OND after recovery and in case of relieving nausea. The severity of nausea was assessed using a visual analogue scale in the 6 and 24 h intervals after drug administration. The SPSS 25.0 statistical software and statistical tests were used to analyze the obtained data. Results: Nanofibers possessed a mean diameter of 159 ± 30 nm beside suitable physicochemical and mechanical characteristics. Statistical evaluations showed that both FDN and ODT formulations had an equal anti-emetic effect (P>0.05) on reducing the severity of nausea but the FDN formulation caused significantly higher levels of patients’ satisfaction (P<0.05) compared to the ODT. Conclusions: Although both formulations had an almost equal anti-emetic effect, due to the benefits of this novel formulation including rapid disintegration, the ODT can be replaced by FDN.

Dioxotriazine derivatives as a new class of P2X3 receptor antagonists: Identification of a lead and initial SAR studies

P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X3 IC50, 16.1 nM; P2X2/3 IC50, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED50, 3.1 mg/kg).