H1 Receptor Binding Research Articles

CP-MLR/PLS directed quantitative structure-activity relationship study on the histamine H3 receptor binding affinity: The cyclohexylamine based series

CP-MLR/PLS directed quantitative structure-activity relationship study on the histamine H3 receptor binding affinity: The cyclohexylamine based series

CP-MLR/PLS directed quantitative structure-activity relationship study on the histamine H3 receptor binding affinity: The cyclohexylamine based series

The histamine H3 receptor binding affinities of cyclohexylamine derivatives has been analysed with the topological and molecular features from Dragon software. Analysis of the structural features in conjunction with the biological endpoints in combinatorial protocol in multiple linear regression (CP-MLR) led to the identification of 26 descriptors for modelling the activity. The study clearly suggested the role of atomic properties such as mass, electronegativity or charge content, polarizability, atomic van der Waals volume, average valence connectivity index chi-5 and absence of number of acceptor atoms for H-bonds (N, O, F) type functionality to optimise the histamine H3 receptor binding affinity of titled compounds. The models developed and the participating descriptors advocate that the substituent groups of the cylohexylamine moiety hold scope for further modification in the optimization of the H3 receptor binding affinity. Analysis of these descriptors in partial least squares (PLS) highlighted their relative significance in modulating the biological response. The selected descriptors are enriched with information corresponding to the activity when compared to the remaining ones. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly.

MACAW: An Accessible Tool for Molecular Embedding and Inverse Molecular Design.

The growing capabilities of synthetic biology and organic chemistry demand tools to guide syntheses toward useful molecules. Here, we present Molecular AutoenCoding Auto-Workaround (MACAW), a tool that uses a novel approach to generate molecules predicted to meet a desired property specification (e.g., a binding affinity of 50 nM or an octane number of 90). MACAW describes molecules by embedding them into a smooth multidimensional numerical space, avoiding uninformative dimensions that previous methods often introduce. The coordinates in this embedding provide a natural choice of features for accurately predicting molecular properties, which we demonstrate with examples for cetane and octane numbers, flash points, and histamine H1 receptor binding affinity. The approach is computationally efficient and well-suited to the small- and medium-size datasets commonly used in biosciences. We showcase the utility of MACAW for virtual screening by identifying molecules with high predicted binding affinity to the histamine H1 receptor and limited affinity to the muscarinic M2 receptor, which are targets of medicinal relevance. Combining these predictive capabilities with a novel generative algorithm for molecules allows us to recommend molecules with a desired property value (i.e., inverse molecular design). We demonstrate this capability by recommending molecules with predicted octane numbers of 40, 80, and 120, which is an important characteristic of biofuels. Thus, MACAW augments classical retrosynthesis tools by providing recommendations for molecules on specification.

Rupatadine – a panacea for allergies? A literature review

Allergic diseases are one of the most common chronic diseases. The incidence of allergies is constantly increasing, and it is currently estimated that around 40% of the population suffers from at least one allergy. Current guidelines for the treatment of allergic rhinoconjunctivitis and urticaria recommend modern second-generation antihistamines. Rupatadine is the first hybrid molecule with high affinity for the H1 receptor resulting from remarkably strong binding to this receptor. It exhibits significant H1 receptor binding selectivity, greater in the lungs than in the cerebellum. It has antihistamine effect that is about 25 and 75 times stronger than that of cetirizine and loratadine, respectively. The second mechanism of its action is a strong antagonism of the platelet-activating factor (PAF) receptor. Rupatadine is rapidly absorbed, which correlates with the onset of anti-H1 and anti-PAF activity. Rupatadine is approximately 99% bound to plasma proteins, but at the same time it is very well distributed to other tissues. It undergoes metabolism in the liver through oxidative processes and glucuronide conjugation. Many studies indicate that rupatadine (10 mg) was at least as effective as desloratadine, cetirizine, loratadine and ebastine in reducing allergic symptoms in allergic rhinitis and urticaria. It has also been confirmed to be effective in relieving the symptoms of insect bite response. Rupatadine has a positive effect on the daily functioning of patients with allergic rhinitis and urticaria, and improves the quality of life of these people. At the same time, many cross-sectional studies have shown that rupatadine has a good safety and tolerability profile in adults and children and has not shown adverse cardiovascular effects.

Histamine Neuroimaging in Stress-Related Disorders.

Although histamine plays a major role in animal models of stress-related disorders, human neuroimaging data are sparse. Histamine H1 receptors in the human brain were first imaged by Professor Kazuhiko Yanai in 1992 by using 11C-doxepin, a potent ligand of H1 receptors, and positron emission tomography (PET). Subsequent work revealed that H1 receptors are reduced in the prefrontal and anterior cingulate cortices in patients with major depressive disorders. A sex difference in H1 receptor binding in the brain has also been found, with women exhibiting more abundant H1 receptor binding than men. Moreover, female patients with anorexia nervosa show higher H1 receptor binding in the amygdala and lentiform nucleus. These studies also found an inverse correlation of depression scores with H1 receptor binding. Histamine is considered to play a major role in the pathophysiology of irritable bowel syndrome (IBS), a representative disorder of brain-gut interactions. Along these lines, hypnotic suggestion dramatically changes the waveforms of viscerosensory cerebral evoked potentials in response to electrical rectal stimulation and these changes are modified by the administration of H1 antagonist. The direction of the H1 antagonist-induced changes in the viscerosensory cerebral evoked potentials differs between IBS patients and healthy controls. Thus, histamine likely plays an important role in stress-related disorders. Further histamine brain imaging studies of humans are warranted.

Synthesis and biological evaluation of novel antipsychotic trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives targeting dopamine/serotonin receptor subtypes

In this study, a series of trans-4-(2-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl)cyclohexan-1-amine derivatives as potential antipsychotics were synthesized and biologically evaluated to discover potential antipsychotics with good drug target selectivity. The preliminary structure-activity relationship was discussed, and optimal compound 12a showed both nanomolar affinity for D2/D3/5-HT1A/5-HT2A receptors and weak α1 and H1 receptor binding affinity. In addition, 12a was metabolically stable in vitro, displayed micromolar affinity for the hERG channel, and exhibited antipsychotic efficacy in the animal model of locomotor-stimulating effects of phencyclidine.

Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers.

Ketotifen (K) and its active metabolite norketotifen (N) exist as optically active atropisomers. They both have antihistaminic and anti-inflammatory properties but the S-atropisomer of N (SN) causes less sedation than K and RN in rodents. This study investigated whether this could be related to a lower concentration of SN in brain or a lower affinity of SN for rat brain H1 receptors. Ketotifen and norketotifen atropisomers were quantified using a validated chiral HPLC assay. RBE4 and Caco-2 cell monolayers were used in uptake and permeability studies, respectively. Free and total brain-to-plasma (B/P) ratios were determined after injecting racemic K and N into rat tail veins. Affinity for rat brain H1 receptors (KI ) was determined using the [3 H]mepyramine binding assay. Uptake and permeation studies indicate no stereoselective transport for K or N. B/P ratios reveal the brain concentration of N is lower than K with no stereoselective transport into brain. Finally, the [3 H]mepyramine binding assay shows SN has the lowest affinity for rat brain H1 receptors. The lower sedative effect of SN in rodents is probably due to a combination of a lower uptake of N than K into the brain and less affinity of SN for CNS H1 receptors.

Association of sleep among 30 antidepressants: a population-wide adverse drug reaction study, 2004-2019.

BackgroundSleep is one of the most essential processes required to maintain a healthy human life, and patients experiencing psychiatric illness often experience an inability to sleep. The aim of this study is to test the hypothesis that antidepressant compounds with strong binding affinities for the serotonin 5-HT2C receptor, histamine H1 receptors, or norepinephrine transporter (NET) will be associated with the highest odds of somnolence.MethodsPost-marketing cases of patient adverse drug reactions were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) during the reporting window of January 2004 to September 2019. Disproportionality analyses of antidepressants reporting somnolence were calculated using the case/non-case method. The reporting odds-ratios (ROR) and corresponding 95% confidence interval (95% CI) were computed and all computations and graphing conducted in R.ResultsThere were a total of 69,196 reported cases of somnolence out of a total of 7,366,864 cases reported from January 2004 to September 2019. Among the 30 antidepressants assessed, amoxapine (n = 16) reporting odds-ratio (ROR) = 7.1 (95% confidence interval [CI] [4.3–11.7]), atomoxetine (n = 1,079) ROR = 6.6 (95% CI [6.2–7.1]), a compound generally approved for attention deficit hyperactivity disorder (ADHD), and maprotiline (n = 18) ROR = 6.3 (95% CI, 3.9–10.1) were the top three compounds ranked with the highest reporting odds of somnolence. In contrast, vortioxetine (n = 52) ROR = 1.3 (95% CI [1.0–1.8]), milnacipran (n = 58) ROR = 2.1 (95% CI [1.7–2.8]), and bupropion (n = 1,048) ROR = 2.2 (95% CI [2.1–2.4]) are least significantly associated with somnolence. Moreover, levomilnacipran (n = 1) ROR = 0.4 (95% CI [0.1–2.9]) was not associated with somnolence.ConclusionAmong the thirty tested antidepressants, consistent with the original hypothesis, amoxepine has strongest 5-HT2C receptor binding affinity and has the highest reporting odds of somnolence. Atomoxetine, ranked second in reporting odds of somnolence overall, binds to the NET with with the strongest binding affinity among the thirty compounds. Mirtazapine, a tetracyclic antidepressant, was ranked 11th in reporting odds of somnolence and had the strongest H1 receptor binding affinity. This study provides an informative ranking of somnolence among thirty antidepressant compounds with an already wide array of clinical indications as well as provides insight into potential drug repurposing in psychopharmacology.

106 – Altered Gender Difference in Brain Histamine H1 Receptor Binding in Patients with Irritable Bowel Syndrome: A Positron Emission Tomography Study

106 – Altered Gender Difference in Brain Histamine H1 Receptor Binding in Patients with Irritable Bowel Syndrome: A Positron Emission Tomography Study

Time-dependent effects of olanzapine treatment on the expression of histidine decarboxylase, H1 and H3 receptor in the rat brain: The roles in olanzapine-induced obesity

Antipsychotic treatment, particularly olanzapine and clozapine, induces severe obesity. The Histamine H1 receptor is considered to be an important contributor to olanzapine-induced obesity, however how olanzapine modulates the histaminergic system is not sufficiently understood. This study examined the effect of olanzapine on key molecules of the histaminergic system, including histidine decarboxylase (HDC), H1 receptor (H1R) and H3 receptor (H3R), in the brain at different stages of olanzapine-induced obesity. During short-term treatment (8-day), olanzapine increased hypothalamic HDC mRNA expression and H1R binding in the arcuate nucleus (Arc) and ventromedial hypothalamus (VMH), without changing H3R binding density. HDC mRNA and Arc H1R binding were positively correlated with increased food intake, feeding efficiency and weight gain. When the treatment was extended to 16 and 36 days, H1R binding was increased not only in the hypothalamic Arc and VMH but also in the brainstem dorsal vagal complex (DVC). The H1R bindings in the Arc, VMH and DVC were positively correlated with weight gain induced by olanzapine treatment. However, the expression of HDC and H3R mRNA was not increased. These results suggest that olanzapine time-dependently modulates histamine neurotransmission, which suggested the different neuronal mechanisms underlying different stages of weight gain development. Treatment targeting the H1R may be effective for both short- and long-term olanzapine-induced weight gain.

The neuroregulation of food intake: The effect of sex on meal selection patterns and the influence of diet on central H1 receptor binding in female SD rats

The neuroregulation of food intake: The effect of sex on meal selection patterns and the influence of diet on central H1 receptor binding in female SD rats

The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands.

In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to 3H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (S1 Table) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. Ab initio quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N–H and O–H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains in silico discrimination between agonists and antagonists based on the receptor structure.

Pharmacoresistant temporal lobe epilepsy modifies histamine turnover and H3 receptor function in the human hippocampus and temporal neocortex

Experiments were designed to evaluate the tissue content of tele-methylhistamine (t-MeHA) and histamine as well as H3 receptor (H3 Rs) binding and activation of the heterotrimeric guanine nucleotide binding αi/o proteins (Gαi/o) coupled to these receptors in the hippocampus and temporal neocortex of patients (n = 10) with pharmacoresistant mesial temporal lobe epilepsy (MTLE). Patients with MTLE showed elevated tissue content of t-MeHA in the hippocampus. Analyses revealed that a younger age at seizure onset was correlated with a higher tissue content of t-MeHA, lower H3 R binding, and lower efficacy of Gαi/o protein activation in the hippocampus. We conclude that the hippocampus shows a reduction in the H3 R function associated with enhanced histamine. In contrast, the temporal neocortex displayed a high efficacy of H3 Rs Gαi/o protein activation that was associated with low tissue contents of histamine and t-MeHA. These results indicate an overactivation of H3 Rs leading to decreased histamine in the temporal neocortex. However, this situation was lessened in circumstances such as a longer duration of epilepsy or higher seizure frequency. It is concluded that decrease in H3 Rs function and enhanced levels of histamine may contribute to the epileptic activity in the hippocampus and temporal neocortex of patients with pharmacoresistant MTLE.

Computational Analysis of Structure-Based Interactions for Novel H₁-Antihistamines.

As a chronic disorder, insomnia affects approximately 10% of the population at some time during their lives, and its treatment is often challenging. Since the antagonists of the H1 receptor, a protein prevalent in human central nervous system, have been proven as effective therapeutic agents for treating insomnia, the H1 receptor is quite possibly a promising target for developing potent anti-insomnia drugs. For the purpose of understanding the structural actors affecting the antagonism potency, presently a theoretical research of molecular interactions between 129 molecules and the H1 receptor is performed through three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. The ligand-based comparative molecular similarity indices analysis (CoMSIA) model (Q2 = 0.525, R2ncv = 0.891, R2pred = 0.807) has good quality for predicting the bioactivities of new chemicals. The cross-validated result suggests that the developed models have excellent internal and external predictability and consistency. The obtained contour maps were appraised for affinity trends for the investigated compounds, which provides significantly useful information in the rational drug design of novel anti-insomnia agents. Molecular docking was also performed to investigate the mode of interaction between the ligand and the active site of the receptor. Furthermore, as a supplementary tool to study the docking conformation of the antagonists in the H1 receptor binding pocket, molecular dynamics simulation was also applied, providing insights into the changes in the structure. All of the models and the derived information would, we hope, be of help for developing novel potent histamine H1 receptor antagonists, as well as exploring the H1-antihistamines interaction mechanism.

Histamine and acetylcholine receptor involvement in sensorimotor gating: an autoradiography study

Sensory gating is a way by which the brain manages sensory information flow. For optimal allocation of neural resources, it is important to be able to screen out (or “gate”) irrelevant sensory information when another stimulus is being processed. Sensorimotor gating more generally refers to the overall process of modulation of the motor responses to sensory stimuli. Impaired sensorimotor gating is seen in a variety of neurobehavioral disorders including schizophrenia, autism and sensory processing disorder. The degree of sensorimotor gating can be studied behaviorally by indexing prepulse inhibition (PPI). PPI reflects the degree of suppression of a startle response to an intense sensory stimulus when it is preceded by a more modest sensory stimulus. The neural circuitry underlying PPI has been shown to include dopaminergic and cholinergic systems. We previously found that histaminergic H1 receptors also play important roles in sensorimotor gating: the acute administration of the histamine H1 antagonist, pyrilamine, significantly reverses the PPI impairment caused by the NMDA glutamate antagonist, dizocilpine (MK-801). The current study was conducted to determine the anatomic bases for histaminergic and cholinergic regulation of the effect of NMDA antagonism on PPI. Using autoradiography, we found that pyrilamine treatment decreased H1 receptor binding in the anterior cingulate, which correlated with PPI improvement. Furthermore, we found that pyrilamine treatment resulted in increased α7-nicotinic acetylcholine receptor binding in the insular cortex, which also correlated with PPI improvement. These findings shed light on the interaction between histamine and acetylcholine signaling in a distributed network of PPI modulation.

Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists

A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure–activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.

Reduction of histamine H1 receptor binding induced by high-fat diet can be prevented by DHA and dietary fiber in specific brain areas of male rats

High-fat (HF) diet and obesity are risk factors for a number of mental health problems including depression, cognitive dysfunction, dementia, and neurodegenerative diseases. Histamine H1 receptors (H1Rs) are involved in many of these conditions. This study examined H1R receptor binding density in the brain of male rats fed a high-saturated fat (HF) diet, as well as the effect of docosahexaenoic acid (DHA), galacto-oligosaccharide (GOS) and resistant starch (RS) supplementation of HF diet. Alterations of H1R expression in the post-mortem rat brain were detected by [(3)H]-pyrilamine binding autoradiography. We found that HF diet significantly decreased H1R binding densities in the substantia nigra (SN), caudate putamen (CPu), hypothalamic arcuate nucleus (Arc), ventral tegmental area (VTA), piriform cortex (Pir) and primary motor cortex (M1), compared with low-fat fed rats, and the suppression of receptor binding density ranged from 31% to 48%. Interestingly, supplementing the HF diet with 0.5% n-3 polyunsaturated docosahexaenoic acid (DHA) prevented reduction of H1R binding densities in the SN and CPu. Addition of galacto-oligosaccharide (GOS) and resistant starch (RS) to the diet blunted HF induced reduction of H1R ligand binding in the SN and Pir, respectively. In conclusion this study showed that HF diet can alter H1R binding densities in various brain regions, and many of these changes can be prevented by adding DHA, GOS or RS to the diet.

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

G-Protein Coupled Receptors (GPCRs) have enormous physiological and biomedical importance, being the primary target of a large number of modern drugs. The availability of structural information of the binding site of the targeted GPCR plays a key role in rationalization, efficiency and cost-effectiveness of the drug discovery process. However, obtaining structural information on GPCRs using X-ray crystallography or NMR requires a large investment of time and is technically very challenging. This situation significantly limits the ability of these methods to have an impact in drug discovery for GPCR targets in the short term and hence there is an urgent need for other effective and cost-efficient alternatives. We present here a practical approach that integrates GPCR modelling with fragment based screening to provide structural insights on the H3 and H4 histamine receptor binding sites. This approach creates a cost-efficient new avenue for structure-based drug design (SBDD) against GPCR targets. We report here a success of using this protocol for the discovery of selective and dual H3 and H4 antagonists. Our fragment screen yielded 44 H3, 21 H4 selective and 20 dual fragment hits. These fragments were used to construct high- quality H3 and H4 models followed by binding site exploration and structure based virtual screening (VS). Overall, 172 compounds were purchased for testing based on the virtual screening results. Of the 74 compounds predicted to have dual activity, 33 had activity against one or other of the two receptors (44%), of which 17 had activity against both. Of the 19 compounds predicted to be H3 selective, 13 were active against H3 (68%) and 10 of these also had selectivity over H4. Of the 79 compounds predicted to be H4 selective, 36 were active against H4 (45%) and 2 of these also had selectivity over H3

Pharmacological characterization of A-960656, a histamine H3 receptor antagonist with efficacy in animal models of osteoarthritis and neuropathic pain

Histamine H3 receptor antagonists have been widely reported to improve performance in preclinical models of cognition, but more recently efficacy in pain models has also been described. Here, A-960656 ((R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)pyridazin-3(2H)-one) was profiled as a new structural chemotype. A-960656 was potent in vitro in histamine H3 receptor binding assays (rat Ki=76nM, human Ki=21nM), and exhibited functional antagonism in blocking agonist-induced [35S]GTPγS binding (rat H3 Kb=107nM, human H3 Kb=22nM), and was highly specific for H3 receptors in broad screens for non-H3 sites. In a spinal nerve ligation model of neuropathic pain in rat, oral doses of 1 and 3mg/kg were effective 60min post dosing with an ED50 of 2.17mg/kg and a blood EC50 of 639ng/ml. In a model of osteoarthritis pain, oral doses of 0.1, 0.3, and 1mg/kg were effective 1h post dosing with an ED50 of 0.52mg/kg and a blood EC50 of 233ng/ml. The antinociceptive effect of A-960656 in both pain models was maintained after sub-chronic dosing up to 12days. A-960656 had excellent rat pharmacokinetics (t1/2=1.9h, 84% oral bioavailability) with rapid and efficient brain penetration, and was well tolerated in CNS behavioral safety screens. In summary, A-960656 has properties well suited to probe the pharmacology of histamine H3 receptors in pain. Its potency and efficacy in animal pain models provide support to the notion that histamine H3 receptor antagonists are effective in attenuating nociceptive processes.

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

The combination of antagonism at histamine H3 receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H3 receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H3 antagonism affinity. However, since all these derivatives failed to block KATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype.