Potent Histamine Research Articles

Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile.

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H3 and H4 receptors (H3R and H4R, respectively). Moreover, we also checked their intrinsic activity toward H3R and muscarinic M1, M2, and M4 receptors (M1R, M2R, and M4R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H3 antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its in vivo efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.

Pharmacokinetics, pharmacodynamics, and safety of izuforant, an H4R inhibitor, in healthy subjects: A phase I single and multiple ascending dose study.

Izuforant is a selective, and potent histamine H4 receptor (H4R) antagonist developed to treat atopic dermatitis (AD). There is an unmet medical need for therapeutic agents to control inflammation and pruritus. Izuforant is a strong candidate for this task based on the findings of non-clinical studies showing that inhibition of the histamine-mediated signaling pathway via H4R by izuforant results in decreased pruritus and inflammation. This study aimed to evaluate the clinical pharmacokinetic (PK) and pharmacodynamic (PD) profiles of izuforant. Dose-block-randomized, double-blind, placebo-controlled, single- and multiple ascending dose studies were conducted in 64 healthy volunteers. For the single ascending dose (SAD) study, 10-600 mg izuforant was administered to the designated groups. For the multiple ascending dose (MAD) study, 100-400 mg izuforant was administered to three groups. The clinical pharmacokinetic (PK) profile of izuforant was evaluated using plasma and urine concentrations. Blood sampling for the PD assay, which measured imetit-induced eosinophil shape changes (ESC), was also conducted. A one-compartment PK model described the distribution and elimination profiles of izuforant. An imetit-induced ESC inhibition test was established and validated for PD evaluation as a measure of the H4R antagonistic effect. ESC inhibition was observed even at doses as low as 10 mg; however, this inhibition became stronger and lasted longer as the dose increased. All izuforant doses were well tolerated, and no discontinuations due to adverse events (AE) or deaths were reported.

Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors.

At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.

Mirtazapine in Primary Insomnia: Case report and Literature review

Introduction: Insomnia is a prevalent sleep disorder characterized by difficulty in falling asleep, maintaining sleep, or achieving restorative sleep, despite adequate opportunities. This condition often results in significant daytime impairments, including fatigue, concentration difficulties, and irritability. Insomnia can be primary or comorbid with other disorders such as anxiety or depression. Case Presentation: A 27-year-old woman presented with severe and chronic insomnia, persisting for 14 years with recent exacerbation. Her symptoms included significant difficulty in initiating and maintaining sleep, resulting in an average of only 3-4 hours of sleep per night and complete sleep deprivation for periods exceeding half an hour over the past 5 days. This sleep deficit led to pronounced emotional instability, physical discomfort, and reduced appetite, although suicidal ideation was absent. She had a past history of drug use for different psychiatric illnesses. She was started on mirtazipine 30mg and showed abrupt improvement in her symptoms. She was discharged afterwards. Discussion: The patient's chronic insomnia and its secondary effects necessitate a comprehensive treatment approach. Mirtazapine, an antidepressant with potent histamine receptor antagonism, has shown efficacy in improving sleep quality across diverse patient profiles. However, side effects like weight gain and sedation require careful monitoring. Combining mirtazapine with prolonged-release melatonin has demonstrated enhanced outcomes, particularly in perimenopausal women. Cognitive Behavioral Therapy for Insomnia (CBT-I) remains the first-line treatment due to its efficacy and long-term benefits. Conclusion: Mirtazapine can be a valuable option in the therapeutic arsenal for primary insomnia, but ongoing research is needed to refine treatment strategies. Personalized treatment plans considering patient history and response are crucial for effectively managing primary insomnia and improving patient outcomes.

Discovery of the novel and potent histamine H1 receptor antagonists for treatment of allergic diseases

Desloratadine, a second-generation histamine H1 receptor antagonist, has established itself as a first-line drug for the treatment of allergic diseases. Despite its effectiveness, desloratadine exhibits an antagonistic effect on muscarinic M3 receptor, which can cause side effects such as dry mouth and urinary retention, ultimately limiting its clinical application. Herein, we describe the discovery of compound Ⅲ-4, a novel H1 receptor antagonist with significant H1 receptor antagonistic activity (IC50 = 24.12 nM) and enhanced selectivity towards peripheral H1 receptor. In particular, Ⅲ-4 exhibits reduced M3 receptor inhibitory potency (IC50 > 10,000 nM) and acceptable hERG inhibitory activity (17.6 ± 2.1 μM) compare with desloratadine. Additionally, Ⅲ-4 exhibits favorable pharmacokinetic properties, as well as in vivo efficacy and safety profiles. All of these reveal that Ⅲ-4 has potential to emerge as a novel H1 receptor antagonist for the treatment of allergic diseases. More importantly, the compound Ⅲ-4 (HY-078020) has recently been granted clinical approval.

Therapeutic effect of rupatadine against l-arginine-induced acute pancreatitis in rats: role of inflammation.

Acute pancreatitis (AP) is an abrupt inflammatory disorder causing high morbidity and mortality. As AP is an insidious medical emergency, a curative modality is required instead of a preventive measure. Thus, we investigated the possible curative effect of rupatadine on a rat model of AP. Rupatadine is a potent histamine receptor 1 (H1R) and platelet-activating factor (PAF) blocker. We used four groups of six Wistar rats as follows: the control group received vehicle; the rupatadine control group received rupatadine as 6mg/kg orally; the AP group received l-arginine intraperitoneally, and the treatment group received rupatadine at 1, 6, and 24h after l-arginine injection. The levels of serum amylase, pancreatic oxidative parameters, and pancreatic cytokines were measured. PAF, histamine, and myeloperoxidase levels were determined in the pancreas. Histopathological and immunohistochemical examinations were performed to determine nuclear factor kappa-B (NF-κB) and caspase 3 expressions. Oxidative damage and severe inflammation were detected in the pancreas of the AP group. Rupatadine reduced the oxidative damage and the levels of proinflammatory cytokines, PAF, histamine, myeloperoxidase, NF-κB, and caspase 3 expressions. It restored the pancreatic acini to almost normal condition. Rupatadine induced important anti-inflammatory and antiapoptotic effects against l-arginine-induced AP.

The functional starter and its genomic insight for histamine degradation in fish sauce

Histamine is a biogenic amine significantly formed in fish sauce leading to a major concern in consumers. This study aimed to identify a halophilic bacterium for histamine degradation in fish sauce, and understand its genomic insight to enhance histamine degradation activity. We discovered the novel halophilic bacterium, Bacillus piscicola FBU1786, degrading histamine and other biogenic amines. Its histamine breakdown was growth-associated in a wide range of NaCl concentrations, pH, and temperature from 4% to 18%, 6.0 to 9.0, and 30 to 45 °C, respectively. Genome sequencing revealed the presence of Cu2+-binding oxidase-encoding genes and their heterologous expression with Cu2+ supplementation triggered histamine degradation in E. coli. The degree of histamine breakdown in B. piscicola FBU1786 could be enhanced by Cu2+ addition. Histamine degradation of the culture was evaluated in raw fish sauce mixtures to partially mimic the condition during fish sauce fermentation. Histamine degradation was suppressed to the extent of raw fish sauce, but could be restored by Cu2+ supplementation. Together, this study disclosed B. piscicola FBU1786 with the potent histamine degradation activity, identified Cu2+-binding oxidases responsible for histamine breakdown, and enhanced histamine degradation of the culture using Cu2+ supplementation.

Drug–drug interaction potential and clinical pharmacokinetics of enerisant, a novel potent and selective histamine H3 receptor antagonist

We evaluated the in vitro drug–drug interaction (DDI) potential of enerisant (TS-091), a histamine H3 receptor antagonist/inverse agonist, mediated by cytochrome P450 (CYP) and transporters, as well as the pharmacokinetics of enerisant in healthy male subjects. Enerisant did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4. Enerisant inhibited organic cation transporter 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2-K, but not P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, or OAT3. Enerisant was a substrate for P-gp, but not for eight other transporters. In healthy male subjects, enerisant was rapidly absorbed after oral administration, and the plasma concentration increased dose-dependently. The urinary excretion of enerisant within 48 h after administration was 64.5% to 89.9% of the dose, indicating that most of the absorbed enerisant was excreted in the urine without being metabolized. Based on the plasma concentrations at the estimated clinical dose, enerisant is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects.

The Functional Starter and its Genomic Insights for Histamine Degradation in Fish Sauce

Histamine is a biogenic amine significantly formed in fish sauce leading to a major concern in consumers. This study aimed to identify a halophilic culture for histamine degradation in fish sauce, and understand its genomic insights to enhance the histamine degradation activity. We discovered the novel halophilic bacterium, Bacillus piscicola FBU1786, degrading histamine and other biogenic amines. Its histamine breakdown was growth-associated in a wide range of NaCl concentrations, pH, and temperature from 4% to 18%, 6.0 to 9.0, and 30 to 45oC, respectively. Genome sequencing revealed the presence of Cu 2+ -binding oxidase-encoding genes and their heterologous expression with Cu 2+ supplementation triggered histamine degradation in E. coli . The degree of histamine breakdown in B . piscicola FBU1786 could be enhanced by Cu 2+ addition. Histamine degradation of the culture was evaluated in raw fish sauce mixtures to partially mimic the condition during fish sauce fermentation. Histamine degradation was suppressed to the extent of raw fish sauce. However, the degradation activity could be restored by Cu 2+ supplementation. Together, this study disclosed B. piscicola FBU1786 with the potent histamine degradation activity, identified Cu 2+ -binding oxidases responsible for histamine breakdown, and enhanced histamine degradation of the culture using Cu 2+ supplementation.

Structural modifications in the distal, regulatory region of histamine H3 receptor antagonists leading to the identification of a potent anti-obesity agent.

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H3 receptor (H3R) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the H3R appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on H3R affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the H3R (Ki=3.17 and 7.70nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H3 receptor. While its structural replacement to piperidine is also tolerated for H3R binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the H3R, as well as drug-like properties of ligands were evaluated using invitro methods. Moreover, pharmacological invivo test results of compound 9 (structural analogue of Abbott's A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound.

Eosinophils adhesion assay as a tool for phenotypic drug screening - The pharmacology of 1,3,5 – Triazine and 1H-indole like derivatives against the human histamine H4 receptor

Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H4 receptor ligands in the treatment of many inflammatory and immunomodulatory diseases, including allergic rhinitis, asthma, atopic dermatitis, colitis or pruritus. Up to date, several potent histamine H4 receptor ligands were developed, none of which was registered as a drug yet. In this study, a series of potent indole-like and triazine derivatives were tested, in radioligand displacement and functional assays at histamine H4 receptor, as well as in human eosinophils adhesion assay to endothelium. For selected compounds permeability, cytotoxicity, metabolic and in vivo studies were conducted. Adhesion assay differentiated the activity of different groups of compounds with a known affinity towards the histamine H4 receptor. Most of the tested compounds downregulated the number of adherent cells. However, adhesion assay revealed additional properties of tested compounds that had not been detected in radioligand displacement and aequorin-based functional assays. Furthermore, for some tested compounds, these abnormal effects were confirmed during the in vivo studies. In conclusion, eosinophils adhesion assay uncovered pharmacological activity of histamine H4 receptor ligands that has been later confirmed in vivo, underscoring the value of well-suited cell-based phenotypic screening approach in drug discovery.

Solid Dispersions of Famotidine: Physicochemical Properties and In Vivo Comparative Study on the Inhibition of Hyperacidity

AbstractFamotidine is a potent histamine 2 antagonist used in the treatment of gastric acid overproduction. Famotidine belongs to Class IV in Biopharmaceutics Classification System (BCS) which has low solubility and membrane permeability. The purpose of this study was to compare the solubility and dissolution profile of solid dispersions (SDs) of famotidine with mannitol (SD‐MAN) and with hydroxypropyl methylcellulose (SD‐HPMC), and to comparatively study their in vivo effectiveness against hyperacidity. Famotidine SDs were prepared by cogrinding technique with the respective carriers in various ratios and grinding time. SDs with the best solubility underwent dissolution rate studies, solid‐state characterization, and in vivo efficacy evaluation. The in vivo evaluation was conducted in Sprague Dawley rats receiving famotidine formulations in the dose equivalent to 12 mg/kg of famotidine. The study found that the famotidine SDs could greatly improve the solubility of famotidine by 100.61 and 120.91% for SD‐MAN and SD‐HPMC, respectively. The solid‐state characterization revealed the decrease in crystallinity degree of famotidine solid dispersion systems. The comparative study on the in vivo efficacy of famotidine SDs showed that SD‐HPMC was significantly better than SD‐MAN. This study concludes that SDs can improve the solubility and in vivo effectiveness of famotidine in overproduction of gastric acid.

0008 SUVN-G3031, A Histamine H3 Receptor Inverse Agonist Produces Robust Wake Promoting and Anticataplectic Activity in Orexin Knockout Mice

Abstract Introduction Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, sleep paralysis, hallucinations, and in some cases episodes of cataplexy. Results from animal studies indicate the involvement of deficient orexin transmission in narcolepsy which can be circumvented by the activation of histaminergic neurons. SUVN-G3031 is a potent and selective histamine H3 receptor inverse agonist with hKi of 8.7 nM and shows less than 50% inhibition at 1 µM against 70 other targets. SUVN-G3031 exhibited excellent pharmacokinetic properties and brain penetration in preclinical species. Oral administration of SUVN-G3031 produces significant increase in histamine, dopamine and norepinephrine levels in the rat cortex. Long-term safety studies in animals have been successfully completed without any concern for further development of SUVN-G3031. In the present study, the effects of SUVN-G3031 were evaluated in orexin knockout mice, a reliable animal model of narcolepsy as a proof-of-concept study for the treatment of narcolepsy with and without cataplexy. Methods Male orexin knockout mice (10 - 15 weeks old, 25 - 35 g at the time of surgery) were implanted with telemetric device for simultaneous monitoring of electroencephalography (EEG) and electromyography. Animals were allowed surgical recovery of 3 weeks prior to EEG recording. Effects of SUVN-G3031 (3 and 10 mg/kg, p.o.) were evaluated during active period of animals. Results SUVN-G3031 produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. SUVN-G3031 also significantly decreased the number of cataplectic episodes in orexin knockout mice. Conclusion Results from the current preclinical study provide a strong basis for the utility of SUVN-G3031 for the treatment of narcolepsy with and without cataplexy. SUVN-G3031 is currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Support None

Pharmacokinetics and Dose Proportionality of Betahistine in Healthy Individuals

Betahistine dihydrochloride is widely used to reduce the severity and frequency of vertigo attacks associated with Ménière’s disease. Betahistine is an analogue of histamine, and is a weak histamine H1 receptor agonist and potent histamine H3 receptor antagonist. The recommended therapeutic dose for adults ranges from 24 to 48 mg given in doses divided throughout the day. Betahistine undergoes extensive first-pass metabolism to the major inactive metabolite 2-pyridyl acetic acid (2PAA), which can be considered a surrogate index for quantitation of the parent drug due to extremely low plasma levels of betahistine. The aim of the present investigation was to assess the pharmacokinetics and dose proportionality of betahistine in Arabic healthy adult male subjects under fasting conditions. A single dose of betahistine in the form of a 8, 16, or 24 mg tablet was administered to 36 subjects in randomized, cross-over, three-period, three-sequence design separated by a one week washout period between dosing. The pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Tmax, and Thalf were calculated for each subject from concentrations of 2-PAA in plasma, applying non-compartmental analysis. The current study demonstrated that betahistine showed linear pharmacokinetics (dose proportionality) in an Arabic population over the investigated therapeutic dose range of 8–24 mg.

Safety, tolerability and pharmacokinetics of a potent and selective histamine h3 receptor inverse agonist, SUVN-G3031 following single and multiple ascending doses in healthy subjects

Safety, tolerability and pharmacokinetics of a potent and selective histamine h3 receptor inverse agonist, SUVN-G3031 following single and multiple ascending doses in healthy subjects

SUVN-G3031, a potent and selective histamine H3 receptor inverse agonist for the treatment of narcolepsy with or without cataplexy – Differentiating factors with competitor clinical candidates

SUVN-G3031, a potent and selective histamine H3 receptor inverse agonist for the treatment of narcolepsy with or without cataplexy – Differentiating factors with competitor clinical candidates

Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivatives as an active and selective histamine H3 receptor ligands

A novel series of 4-pyridylpiperazine derivatives with varying alkyl linker length and eastern part substituents proved to be potent histamine H3 receptor (hH3R) ligands in the nanomolar concentration range. While paying attention to their alkyl linker length, derivatives with a six methylene linker tend to be more potent than their five methylene homologues. Moreover, in the case of both phenoxyacetyl- and phenoxypropionyl- derivatives, an eight methylene linkers possess lower activity than their seven methylene homologues. However, in global analysis of collected data on the influence of alkyl linker length, a three methylene homologues appeared to be of highest hH3R affinity among all described 4-pyridylpiperazine derivatives from our group up to date. In the case of biphenyl and benzophenone derivatives, compounds with para- substituted second aromatic ring were of higher affinity than their meta analogues. Interestingly, benzophenone derivative 18 showed the highest affinity among all tested compounds (hH3R Ki = 3.12 nM). The likely protein-ligand interactions, responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at H3R, as well as drug-like properties of selected ligands were evaluated using in vitro methods.

0120 SUVN-G3031, a Novel, Potent and Selective Histamine H3 Receptor Inverse Agonist for the Treatment of Narcolepsy: Preclinical Characterization

0120 SUVN-G3031, a Novel, Potent and Selective Histamine H3 Receptor Inverse Agonist for the Treatment of Narcolepsy: Preclinical Characterization

0139 SUVN-G3031, A Potent and Selective Histamine H3 Receptor Inverse Agonist - Phase-2 Investigational New Drug for the Treatment of Narcolepsy - Differentiating Factors with Competitor Clinical Candidates

0139 SUVN-G3031, A Potent and Selective Histamine H3 Receptor Inverse Agonist - Phase-2 Investigational New Drug for the Treatment of Narcolepsy - Differentiating Factors with Competitor Clinical Candidates

0053 SUVN-G3031: Safety, Tolerability and Pharmacokinetics of a Potent and Selective Histamine H3 Receptor Inverse Agonist - Single and Multiple Ascending Doses in Healthy Subjects

0053 SUVN-G3031: Safety, Tolerability and Pharmacokinetics of a Potent and Selective Histamine H3 Receptor Inverse Agonist - Single and Multiple Ascending Doses in Healthy Subjects