H2-antagonist Activity Research Articles

QSAR and Molecular Docking Studies on Non-Imidazole-Based Histamine H3 Receptor Antagonists

Background: In the recent years, histamine H3 receptor (H3R) has been receiving increasing attention in pharmacotherapy of neurological disorders. The aim of the current study was to investigate structural requirements for the prediction of H3 antagonistic activity using quantitative structure-activity relationship (QSAR) and molecular docking techniques. Methods: To this end, genetic algorithm coupled partial least square and stepwise multiple linear regression methods were employed for developing a QSAR model. The obtained QSAR model was stringently assessed using different validation criteria. Results: The generated model indicated that connectivity information and mean absolute charge are two important descriptors for the prediction of H3 antagonistic activity of the studied compounds. To gain insight into the mechanism of interaction between studied molecules and H3R, molecular docking was performed. The most important residues involved in the ligand-receptor interactions were identified. Conclusion: The result of current study can be used for designing of new H3 antagonist and proposing structural modifications to improve H3 inhibitory potency.

Design, synthesis and biological evaluation of novel desloratadine derivatives with anti-inflammatory and H1 antagonize activities

To improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H1 antagonistic activities. Among them, compound 2c showed the strongest H1 antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.

Search for multifunctional agents against Alzheimer’s disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives

In the search for new treatments for complex disorders such as Alzheimer’s disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood–brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2 = 8.27), inhibitory activity against both AChE (IC50 = 13.96 μM), and BuChE (IC50 = 14.62 μM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.

Non-Imidazole Histamine H₃ Ligands. Part VII. Synthesis, In Vitro and In Vivo Characterization of 5-Substituted-2-thiazol-4-n-propylpiperazines.

H3 receptors present on histaminergic and non-histaminergic neurons, act as autoreceptors or heteroreceptors controlling neurotransmitter release and synthesis. Previous, studies have found that the compound N-methyl-N-3-phenylalkyl-2-[2-(4-n-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethan-1-amine (ADS-531, 2c) exhibits high in vitro potency toward H3 guinea pig jejunal receptors, with pA2 = 8.27. To optimize the structure of the lead compound ADS-531, a series of 5-substituted-2-thiazol-4-n-propylpiperazines 3 were synthesized and subjected to in vitro pharmacological characterization; the alkyl chain between position 2 of the thiazole ring and the terminal secondary N-methylamino function was elongated from three to four methylene groups and the N-methylamino functionality was substituted by benzyl-, 2-phenylethyl-, and 3-phenyl-propyl- moieties. SAR studies on novel non-imidazole, 5-substituted-2-thiazol-4-n-propyl-piperazines 3 showed that the most active compound 3a (pA2 = 8.38), additionally possessed a weak competitive H1-antagonistic activity. Therefore, compound ADS-531, which did not exhibit any H1-antagonistic activity, was chosen for further evaluation for its affinity to the recombinant rat and human histamine H3 receptors (rH3R and hH3R, respectively). ADS-531 exhibited nanomolar affinity for both rH3R and hH3R receptors. It was also shown that, ADS-531 given subchronically to rats (s.c. 3 mg/kg, 5 days) penetrated the brain, where it affected dopamine, noradrenaline and serotonin concentration; however, it did not affect histamine concentration nor feeding behavior.

Non-Imidazole Histamine H3 Ligands. Part VI. Synthesis and Preliminary Pharmacological Investigation of Thiazole-Type Histamine H3-Receptor Antagonists with Lacking a Nitrogen Nucleus in the Side Chain.

Antagonists to the H3 receptor are considered to be potential drugs for the treatment of Alzheimer's disease, attention deficit-hyperactive disorder, memory and learning deficits, and epilepsy. The initial development of potent H3 receptor antagonists focused on extensive modification of the natural ligand histamine. However, it has appeared that imidazole-containing ligands are associated with inhibition of cytochrome P450 enzymes, caused by imidazole nitrogen complexation to heme iron in the active site of the enzyme. For these reasons, the development of potent non-imidazole H3receptor antagonists was eagerly awaited. Previously, we reported the synthesis and pharmacological in vitro characterization of series of potent histamine H3receptor non-imidazole antagonists belonging to the class of substituted 2-thiazol-4-n-propylpiperazines. A lead compound 1 of this family was a derivative carrying the ethylaminomethylpropyl chain. With the aim of increasing lipophilicity, that will help the ligands to cross the blood-brain barrier, we synthesized a series of new 2-thiazol-4-n-propylpiperazines where the ethylaminomethylpropyl moiety was replaced by a p-substituted-, an unsubstituted benzene ring, and ω-phenylalkyl substituent at positions 4 and 5 of thiazole ring, respectively. All compounds were tested for H3 antagonistic effects in vitro using the electrically contracting guinea pig jejunum. The most active compounds of presented series 3d, 3e, and 3j showed lower affinity than the lead compound 1 and additionally, derivatives 3d and 3j possessed weak, competitive H1 antagonistic activity. This is in contrast to the lead compound 1 that has no affinity at H1 receptor. We can conclude that a side chain in the 2-thiazol-4-n-propylpiperazine scaffold should contain a basic center and should be present at a favorable position 5 of thiazole ring.

QSAR and Pharmacophore Analysis of a Series of Piperidinyl Urea Derivatives as hERG Blockers and H3 Antagonists

In the present study, a computational based pharmacophore and structural analysis were performed on a series of piperidinyl urea derivatives, a limited number of compounds which have variation in structures and activities that exhibit hERG blocking and H3 antagonistic activities. The conducted QSAR studies demonstrated that the developed models are statistically significant, which have been confirmed through validation. The Q2 values for the models developed with hERG blocking activity are > 0.8 and with the H3 antagonistic activity are > 0.6. The descriptors contributed in the models show that the distributed polar properties on the vdW surface of the molecules are important for the hERG blocking activity. The vsurf_ descriptors (surface area, volume and shape) such as vsurf_DD13 and vsurf_Wp4 correlate with the H3 antagonistic activity of these compounds. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor (acc), donor (don), hydrophobic (hyd) and aromatic/hydrophobic (aro/hyd) pharmacophore properties are favorable contours sites for both the activities. Also, our study reveals that the distance between the polar contours (acc, don, etc) has to be small for better hERG blocking activity. The distances between the aro/hyd to the polar groups should be higher for better hERG blocking activity. However, the H3 antagonistic activity for these series depends upon hydrophobic property of the molecules, particularly the hyd and the hyd/aro contours of the molecules. Hence, these results reveal the requirements on the structural properties and the distances between the pharmacophore contour sites of the molecules responsible for their hERG and H3 antagonistic activities.

Blonanserin, an Antipsychotic and Dopamine D2/D3 Receptor Antagonist, and Ameliorated Alcohol Dependence

Blonanserin (BNS) is used for treatment of both positive and negative symptoms of schizophrenia in Japan and Korea. Because BNS has weak α1 receptor blocking activities and is almost devoid of histamine H1 and muscarinic M1 antagonist activity, BNS is better tolerated than other atypical antipsychotics. A high degree of D₃ receptor blockage is reported to be predictive of drug abuse and alcoholism, and BNS has strong D₃ receptor antagonism. Thus, BNS may be useful in the treatment of alcoholism. We present a case in which BNS ameliorated alcohol dependence.

QSAR and Pharmacophore Analysis of a Series of Piperidinyl Urea Derivatives as hERG Blockers and H3 Antagonists

In the present study, a computational based pharmacophore and structural analysis were performed on a series of piperidinyl urea derivatives, a limited number of compounds which have variation in structures and activities that exhibit hERG blocking and H3 antagonistic activities. The conducted QSAR studies demonstrated that the developed models are statistically significant, which have been confirmed through validation. The Q2 values for the models developed with hERG blocking activity are >0.8 and with the H3 antagonistic activity are >0.6. The descriptors contributed in the models show that the distributed polar properties on the vdW surface of the molecules are important for the hERG blocking activity. The vsurf_ descriptors (surface area, volume and shape) such as vsurf_DD13 and vsurf_Wp4 correlate with the H3 antagonistic activity of these compounds. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor (acc), donor (don), hydrophobic (hyd) and aromatic/hydrophobic (aro/hyd) pharmacophore properties are favorable contours sites for both the activities. Also, our study reveals that the distance between the polar contours (acc, don, etc) has to be small for better hERG blocking activity. The distances between the aro/hyd to the polar groups should be higher for better hERG blocking activity. However, the H3 antagonistic activity for these series depends upon hydrophobic property of the molecules, particularly the hyd and the hyd/aro contours of the molecules. Hence, these results reveal the requirements on the structural properties and the distances between the pharmacophore contour sites of the molecules responsible for their hERG and H3 antagonistic activities. Keywords: hERG, H3 antagonistic, pharmacophore, piperidinyl urea, QSAR

1-Phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl]piperazine derivatives as non-imidazole histamine H3-antagonists

In this study, a series of 1-phenoxyalkyl-4-[(N,N-disubstitutedamino)alkyl]piperazine derivatives has been prepared and in vitro tested as H3-receptor antagonists (electrically evoked contraction of the guinea pig jejunum). All compounds investigated show moderate in vitro affinities. The most potent antagonists in this series are the compounds 9b, 1b, 1f, and 1l, which exhibit, independently of the substituent at the end of -N- moiety, almost the same level of affinity (pA2 = 7.18, pA2 = 7.27, pA2 = 7.13, pA2 = 7.12, respectively). The histaminergic H1 antagonism of the aforementioned four products was established on the isolated guinea pig ileum by conventional methods; the pA2 values were compared with the potency of pyrilamine. None of them shows any H1-antagonistic activity (pA2 < 4; for pyrilamine pA2 = 9.35).

Synthesis and structure–activity relationship (SAR) study of 4-azabenzoxazole analogues as H3 antagonists

The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H3 antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H3 antagonist activity in both ex vivo and in vivo assays.

Design, synthesis and antihistaminic (H1)activity of some condensed 2-(substituted)arylaminoethylpyrimidin-4(3H)-ones.

The synthesis and potential H1 receptor antagonistic activity of two novel series of condensed 2-arylaminoethylpyrimidin-4(3H)-ones (4, 5) and 4-amino-2-arylaminoethyl pyrimidines (6) have been reported. All the novel compounds were found to antagonize histamine in a competitive and reversible manner. When tested on guinea-pig ileum, compounds exhibited H1-antagonistic activity, (pA2 values) in the range of 8.6 to 9.7. Some of the lead compounds were evaluated by an in vivo method and were found to protect the guinea pigs against the histamine induced asphyxic shock at the doses comparable to or lower than those of the standard drugs, cetirizine (CAS 83881-51-0) and terfenadine (CAS 50679-08-8). The pA2 acetylcholine values of some of the lead compounds reflect about 1000-fold selectivity for histamine (H1) receptors. The 4-aminopyrimidines (6) were found to be more selective than their 4-one analogs (4, 5). In the radioligand binding study, one of the lead compounds, 6e, was found to bind reversibly at the histamine H1 receptor with the K1 value of 1.3 mumol/l and IC50 of 3.8 mumol/l. The lead compounds were found to have negligible sedative potential when tested in vivo. An indirect type of molecular modeling approach, using temelastine (CAS 86181-42-2) as the standard ligand, indicates that the potent activity of 4, 5 and 6 may be due to the increased spacer chain length between the pyrimidine nucleus and the side-chain aromatic ring.

Pharmacological Profile of New Histamine H2-Receptor Antagonists Related to Cimetidine, Ranitidine and Lamtidine

New compounds structurally related to cimetidine, ranitidine and lamtidine have been prepared and tested for their histamine H2-receptor blocking activity on guinea-pig atria, rat perfused stomach and frog isolated gastric mucosa. These derivatives contain as a polar group, a diaminofurazan moiety, a 3-amino-4-methylfurazan or a 3-amino-4-phenylfurazan moiety. Ranitidine and lamtidine analogues display strong H2-antagonist activity in-vitro (KB on atria 0.037 microM and 0.0039 microM, respectively) and in-vivo on the lumen-perfused stomach of the anaesthetized rat (ID50 0.13 mumol kg-1 and 0.023 mumol kg-1 i.v., respectively). However, lamtidine analogues are ineffective in blocking the histamine-induced increase of H+ output in the frog isolated gastric mucosa. On the basis of the anomalous results in the frog, it is concluded that caution must be exercised in extrapolating information from amphibian to mammalian tissues with regard to the structure and the function of histamine receptors.

Modelling of serotonin reuptake inhibitory and histamine H3 antagonistic activity of piperazine and diazepane amides: QSAR rationales for co-optimization of the activity profiles

Selective human serotonin reuptake transporter (hSERT) inhibition is the first line of treatment to deal with the depression. In clinical practice for managing depression, the stimulants are co-prescribed to overcome cognitive impairment and fatigue. Recently, histamine H3 antagonists with serotonin reuptake inhibition activity have been proposed as alternative approach for the treatment of depression. In this context, a QSAR study of hSERT inhibitory and H3 antagonistic activity of piperazine and diazepane amide derivatives has been carried out using the combinatorial protocol in multiple linear regression (CP-MLR) with 0D- to 2D-Dragon descriptors. The derived QSAR models have provided a rational approach for the development of new piperazine and diazepane amide derivatives as hSERT inhibitors and H3 antagonists. In a concomitant partial least-squares (PLS) analysis of the hSERT and histamine H3 activities, the fraction contributions of identified descriptors revealed their importance in modulating these activities. The PLS analysis of other biological endpoints, namely hNET, hDAT, and histamine H3 activity in functional assay (H3pA2) of these analogues with the identified descriptors has further highlighted their scope in modulating these activities.

Brain histamine H1 receptor occupancy of loratadine measured by positron emission topography: comparison of H1 receptor occupancy and proportional impairment ratio

We have evaluated the sedative properties of H1-antihistamines by using positron emission tomography (PET) and ¹¹C-doxepin. The purpose of the present study was to measure histamine H1 receptor occupancy (H1RO) of loratadine 10 mg in patients with allergic rhinitis and to compare this occupancy with that of d-chlorpheniramine 2 mg, a first-generation antihistamine. We also compared our PET findings with the proportional impairment ratio reported by McDonald et al. The H1RO of loratadine 10 mg and d-chlorpheniramine 2 mg were evaluated in human brains in a double-blind and crossover design using ¹¹C-doxepin PET. Eleven young male patients with allergic rhinitis were examined by PET following oral single administration of loratadine 10 mg and d-chlorpheniramine 2 mg. Loratadine 10 mg occupied 11.7 ± 19.5% of histamine H1 receptors in the cortex, whereas d-chlorpheniramine 2 mg occupied 53.0 ± 33.2% in the same area, suggesting a non-sedating property of loratadine at a dose of 10 mg. The H1RO values of loratadine and d-chlorpheniramine as well as those of previous studies were found to be significantly proportional to the proportional impairment ratio (r = 0.899). Measurement of H1RO is a sensitive and absolute method to characterize the non-sedating property of drugs with H1 antagonistic activity.

ChemInform Abstract: Histamine Analogues: Imidazolylalkylguanidines. Synthesis and in vitro Pharmacology.

Impromidine analogues characterized by modified side chains connecting the guanidine and imidazole moieties have been prepared and tested for H2-agonistic activity on isolated guinea-pig right atrium and for H1-antagonistic activity on guinea-pig ileum, respectively. 3-(1H-Imidazol-4-yl)propylguanidines with varied cimetidine-like side chain (5a–d) proved to be almost full H2-agonists and 5–70 times more potent than histamine, whereas compounds with β- or γ-methyl branched imidazolylpropyl moiety (5e, 5f, 5h) are only weak partial H2-agonists. Both unsaturated impromidine analogues (5i, 5j) are full H2-agonists, the (Z)-configurated compound 5j being about 4 times more potent than the (E)-configurated derivate 5i.

Reduction of hERG inhibitory activity in the 4-piperidinyl urea series of H3 antagonists

Structural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure–activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed.

Enantioseparation of cetirizine by chromatographic methods and discrimination by 1H‐NMR

Cetirizine is an antihistaminic drug used to prevent and treat allergic conditions. It is currently marketed as a racemate. The H1-antagonist activity of cetirizine is primarily due to (R)-levocetirizine. This has led to the introduction of (R)-levocetirizine into clinical practice, and the chiral switching is expected to be more selective and safer. The present work represents three methods for the analysis and chiral discrimination of cetirizine. The first method was based on the enantioseparation of cetirizine on silica gel TLC plates using different chiral selectors as mobile phase additives. The mobile phase enabling successful resolution was acetonitrile-water 17: 3, (v/v) containing 1 mM of chiral selector, namely hydroxypropyl-beta-cyclodextrin, chondroitin sulphate or vancomycin hydrochloride. The second method was a validated high performance liquid chromatography (HPLC), based on stereoselective separation of cetirizine and quantitative determination of its eutomer (R)-levocetirizine on a monolithic C18 column using hydroxypropyl-beta-cyclodextrin as a chiral mobile phase additive. The resolved peaks of (R)-levocetirizine and (S)-dextrocetirizine were confirmed by further mass spectrometry. The third method used a (1)H-NMR technique to characterize cetirizine and (R)-levocetirizine. These methods are selective and accurate, and can be easily applied for chiral discrimination and determination of cetirizine in drug substance and drug product in quality control laboratory. Moreover, chiral purity testing of (R)-levocetirizine can also be monitored by the chromatographic methods.

The Role of Antihistamines in the Treatment of Vasomotor Rhinitis

Background: The pathogenesis of vasomotor rhinitis is not understood. It is unlikely that antihistamines, based on their H1 antagonist activity alone, would be effective in this disorder.Methods: Nonetheless, at least one double-blind, placebo-controlled multicenter trial has found that intranasal azelastine relieves symptoms of this disorder better than placebo. The mechanism responsible for its beneficial effect in nonallergic rhinitis is unclear but probably relates to "anti-inflammatory/antiallergic" activities.Results: Such mechanisms have been demonstrated for a number of different oral antihistamines, but often the concentrations required in vitro are higher than those that are normally achieved in vivo using recommended dosing. It has been postulated that intranasal administration, which can achieve high local levels, might be a factor responsible for enhancing the "anti-inflammatory/antiallergic" properties.Conclusions: Interpreting this information allows one to conclude that antihistamines may be potentially effective agents in vasomotor rhinitis, and are more likely to be so when administered intranasally, despite the fact that data documenting this beneficial effect are sparse.

Betahistine: what's new on the agenda?

Background: Betahistine is an orally administered, centrally acting histamine H1 receptor agonist with partial H3 antagonistic activity and no H2–binding effects. In the past betahistine was clinically studied mainly as a vasodilator for conditions such as cluster headaches, vascular dementia and Meniere's disease, for which it is still used. In recent years, histamine was found to be a key neurotransmitter in the regulation of feeding behavior. Objective: To provide a review of the developmental history and current research interests of betahistine. Methods: All reports of betahistine use in animals and humans were retrieved and reviewed. Results/conclusion: The unique pharmacologic properties of betahistine point to its potential future use as an antiobesity agent.

Molecular modeling of histamine H3 receptor and QSAR studies on arylbenzofuran derived H3 antagonists

Histamine H3 receptors are presynaptic autoreceptors found in both central and peripheral nervous systems of many species. The central effects of these receptors suggest a potential therapeutic role for their antagonists in treatment of several neurological disorders such as epilepsy, schizophrenia, Alzheimer's and Parkinson's diseases. The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure–activity relationship (QSAR) studies and receptor modeling/docking techniques. A combination of partial least squares (PLS) and genetic algorithm (GA) was used in the QSAR approach to select the structural descriptors relevant to the receptor binding affinity of a series of 58 H3 antagonists. The descriptors were selected out of a pool of >1000 descriptors calculated by DRAGON, Hyperchem and ACD labs suite of programs. The resulting QSAR models for rat and human H3 binding affinities were validated using different strategies. QSAR models generated in the current work suggested the role of charge transfer interactions in the ligand–receptor interaction verified using the molecular modeling of the receptor and docking two antagonists to the binding site. The 3D model of human H3 receptor was built based on bovine rhodopsin structure and evaluated by molecular dynamics (MD) simulation in a mixed water–vacuum–water environment. The results were indicative of the stability of the model relating the observed structural changes during the MD simulation to the suggested ligand–receptor interactions. The results of this investigation are expected to be useful in the process of design and development of new potent H3 receptor antagonists.