thioperamide and ciproxifan

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H

Topics: Animals; Anti-Obesity Agents; Body Weight; Dose-Response Relationship, Drug; Female; Histamine H3 Antagonists; Humans; Imidazoles; Ligands; Models, Molecular; Piperazine; Piperidines; Protein Binding; Rats, Wistar; Receptors, Histamine H3; Regulatory Sequences, Nucleic Acid; Structure-Activity Relationship

G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that play important role in regulating key physiological functions, and are targets of about 50% of all recently launched drugs. High-resolution experimental structures are available only for very few GPCRs. As a result, structure-based drug design efforts for GPCRs continue to rely on in silico modeling, which is considered to be an extremely difficult task especially for these receptors. Here, we describe Gmodel, a novel approach for building 3D atomic models of GPCRs using a normal mode-based refinement of homology models. Gmodel uses a small set of relevant low-frequency vibrational modes derived from Random Elastic Network model to efficiently sample the large-scale receptor conformation changes and generate an ensemble of alternative models. These are used to assemble receptor-ligand complexes by docking a known active into each of the alternative models. Each of these is next filtered using restraints derived from known mutation and binding affinity data and is refined in the presence of the active ligand. In this study, Gmodel was applied to generate models of the antagonist form of histamine 3 (H3) receptor. The validity of this novel modeling approach is demonstrated by performing virtual screening (using the refined models) that consistently produces highly enriched hit lists. The models are further validated by analyzing the available SAR related to classical H3 antagonists, and are found to be in good agreement with the available experimental data, thus providing novel insights into the receptor-ligand interactions.

Topics: Amino Acid Sequence; Drug Discovery; Histamine H3 Antagonists; Humans; Imidazoles; Ligands; Models, Molecular; Molecular Sequence Data; Oximes; Piperidines; Protein Binding; Receptors, G-Protein-Coupled; Receptors, Histamine H3; Sequence Alignment; Thiourea

Accumulated evidence suggests a role for histamine in cognition and the use of H3 receptor antagonists in the treatment of learning and memory disorders.. The aim of the current study was to investigate the cognition enhancing properties of ciproxifan, an H3 receptor antagonist, after natural forgetting in normal adult rats.. The novel object discrimination task, a recognition memory test based on spontaneous exploratory behaviour, was used. Briefly, rats exposed to two identical objects during an acquisition trial can discriminate between a novel object and a familiar one during a subsequent choice trial after a short delay but not after a 24-h inter-trial interval.. The scopolamine (0.5 mg/kg, i.p.)-induced impairment after a short delay was abolished by ciproxifan (p < 0.001). Natural forgetting was prevented by a single administration of ciproxifan (3 mg/kg) prior to the retention test (p < 0.001) but not when administered before or immediately after the acquisition trial (schedule effect p < 0.05), demonstrating a specific activity on memory retrieval. Pretreatment with either pyrilamine (10 mg/kg), an H1 antagonist, or zolantidine (10 mg/kg), an H2 antagonist, prevented the retrieval enhancement effect of ciproxifan (p < 0.05 and p < 0.001, respectively).. Histamine H3 receptor antagonists restore the performance of rats impaired by scopolamine and enhance recognition memory after acute administration before the retrieval phase via a mechanism dependent on H1 and H2 receptor activation.

Topics: Animals; Discrimination Learning; Discrimination, Psychological; Exploratory Behavior; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine H3 Antagonists; Histamine Release; Imidazoles; Male; Memory; Mental Recall; Muscarinic Antagonists; Piperidines; Psychomotor Performance; Rats; Rats, Wistar; Recognition, Psychology; Scopolamine

Preclinical findings demonstrate procognitive actions of histamine 3 (H3) receptor antagonists/inverse agonists. Since a prominent role of neuronal network oscillations of the hippocampus, such as theta band oscillation, has been recognized in numerous cognitive functions, in the present study, the potential involvement of H3 receptors in modulation of hippocampal theta activity has been investigated using various recording paradigms. Systemic administration of the selective H3 receptor antagonists/inverse agonists, thioperamide and ciproxifan (0.1 mg/kg to 1 mg/kg i.v.), dose dependently increased hippocampal theta power, similarly to methylphenidate (0.1-1 mg/kg i.v.), in chloral hydrate anesthetized rats. When hippocampal theta oscillation was elicited by electrical brainstem (nucleus pontis oralis) stimulation, ciproxifan (1 mg/kg i.v.) augmented the power of stimulation-induced theta. In contrast, systemic administration of methylphenidate (1 mg/kg i.v.) did not modify elicited theta. To analyze the role of H3 receptors on stage- and behavior-dependent hippocampal theta activity, polysomnographic recordings were carried out together with field potential recordings at the hippocampal fissure in freely moving rats for 8 h during the light phase of the circadian cycle. Systemic administration of ciproxifan (3.0 mg/kg, i.p.) promoted wakefulness with a concomitant reduction in cortical delta power and augmented novelty-induced hippocampal theta activity. These findings provide evidence that H3 receptors play an important role in regulation of hippocampal theta oscillation, representing one of the probable mechanisms involved in histamine-induced modulation of higher brain functions, such as attention and learning.

Topics: Anesthetics; Animals; Central Nervous System Stimulants; Chloral Hydrate; Electroencephalography; Electromyography; Hippocampus; Histamine H3 Antagonists; Imidazoles; Male; Methylphenidate; Muscle, Skeletal; Neck; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Theta Rhythm; Urethane

Despite the well-described attention and short-term memory enhancing effects of H3 receptor antagonists, and evidence to suggest a close relationship between central histaminergic and cholinergic systems, there is a paucity of evidence for a role for H3 receptor blockade in spatial learning. To address this, we investigated two H3 receptor antagonists in a visual discrimination water maze in rats, and in a Barnes circular maze in mice. Thioperamide and ciproxifan significantly attenuated a scopolamine-induced deficit in the water maze task, while only ciproxifan showed a modest attenuation in the Barnes maze. Taken together, these data suggest a role for H3 receptors in spatial learning that appears to be task-dependent.

Topics: Animals; Cognition Disorders; Discrimination Learning; Escape Reaction; Histamine Antagonists; Imidazoles; Male; Maze Learning; Mice; Mice, Inbred C57BL; Models, Animal; Muscarinic Antagonists; Piperidines; Rats; Rats, Long-Evans; Receptors, Histamine H3; Scopolamine; Spatial Behavior

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.

Topics: Animals; Antipsychotic Agents; Benzofurans; Brain Chemistry; Cataplexy; Cytochrome P-450 Enzyme System; Drug Combinations; Drug Synergism; Haloperidol; Histamine; Histamine Antagonists; Imidazoles; Ketoconazole; Male; Metabolic Clearance Rate; Piperidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Risperidone; Schizophrenia

Histamine H3 receptor antagonists/inverse agonists have been proposed as potential therapeutic agents for the treatment of a number of neurological disorders ranging from attention deficit hyperactivity disorder and Alzheimer's disease to narcolepsy and schizophrenia. With respect to the latter, schizophrenic patients typically exhibit impaired prepulse inhibition (PPI) of startle, a reflex that can be modeled in many animal species. Certain strains of mice naturally display poor PPI and it was recently suggested that these mice might offer a new way to screen for novel antipsychotic compounds. To examine whether H3 receptor antagonists might enhance PPI in mice with naturally occurring deficits, DBA/2 and C57BL/6 were tested in a startle paradigm with three prepulse intensities: 5, 10 and 15 dB above background. Both thioperamide and ciproxifan enhanced PPI in the DBA/2 strain; thioperamide also showed a trend towards enhancing PPI in C57BL/6. Risperidone, an atypical antipsychotic, enhanced PPI in both the DBA/2 and the C57BL/6 strain. These data confirm previous reports describing a natural deficit in PPI in some mouse strains that is amenable to enhancement with known antipsychotics. Further, these data suggest that H3 receptor antagonists/inverse agonists have anti-psychotic potential for disorders such as schizophrenia.

Topics: Acoustic Stimulation; Animals; Dopamine Antagonists; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Histamine Antagonists; Imidazoles; Inhibition, Psychological; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Piperidines; Receptors, Histamine H3; Reflex, Startle; Risperidone; Species Specificity

The effects of histaminergic ligands on both ACh spontaneous release from the hippocampus and the expression of c-fos in the medial septum-diagonal band (MSA-DB) of freely moving rats were investigated. Because the majority of cholinergic innervation to the hippocampus is provided by MSA-DB neurons, we used the dual-probe microdialysis technique to apply drugs to the MSA-DB and record the induced effects in the projection area. Perfusion of MSA-DB with high-KCl medium strongly stimulated hippocampal ACh release which, conversely, was significantly reduced by intra-MSA-DB administration of tetrodotoxin. Histamine or the H2 receptor agonist dimaprit, applied directly to the hippocampus, failed to alter ACh release. Conversely, perfusion of MSA-DB with these two compounds increased ACh release from the hippocampus. Also, thioperamide and ciproxifan, two H3 receptor antagonists, administered into MSA-DB, increased the release of hippocampal ACh, whereas R-alpha-methylhistamine, an H3 receptor agonist, produced the opposite effect. The blockade of MSA-DB H2 receptors, caused by local perfusion with the H2 receptor antagonist cimetidine, moderated the spontaneous release of hippocampal ACh and antagonized the facilitation produced by H3 receptor antagonists. Triprolidine, an H1 receptor antagonist, was without effect. Moreover, cells expressing c-fos immunoreactivity were significantly more numerous in ciproxifan- or thioperamide-treated rats than in controls, although no colocalization of anti-c-fos and anti-ChAT immunoreactivity was observed. These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus.

Topics: Acetylcholine; Animals; Hippocampus; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Imidazoles; Male; Microdialysis; Neurons; Perfusion; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Histamine H3; Septal Nuclei; Tetrodotoxin; Triprolidine

Different histamine H3-receptor antagonists have been tested in displacement studies at human and rat H3 receptors in stably transfected cells. Based on an actual rhodopsin structure, models for receptor antagonist interaction were developed for receptors of both species. Similarities and discrepancies in binding profiles can be explained, but not quantified by hydrophilic interactions with Asp114 and an important lipophilic binding pocket modified by two nearby amino acids.

Topics: Animals; CHO Cells; Cricetinae; Female; Histamine Antagonists; Humans; Imidazoles; Models, Molecular; Protein Binding; Rats; Receptors, Histamine H3; Rhodopsin; Species Specificity

Novel histamine H(3)-receptor antagonists possessing a 4-(3-(phenoxy)propyl)-1H-imidazole structure generally substituted in the para-position of the phenyl ring have been synthesized according to Mitsunobu or S(N)Ar reactions. With in vitro and in vivo screening for H(3)-receptor antagonist potency, the carbonyl-substituted derivatives proved to be highly active compounds. A number of compounds showed in vitro affinities in the subnanomolar concentration range, and the 4-hexanoyl (10) and 4-acetyl-3-methyl (29) substituted derivatives showed in vivo antagonist potencies of about 0.1 mg/kg after po administration. Many proxifans were also tested for their affinities at other histamine receptor subtypes thereby demonstrating their pronounced H(3)-receptor subtype selectivity. Since the cyclopropyl ketone derivative 14 (ciproxifan) had high affinity in vitro as well as high potency in vivo, it was selected for further studies in monkeys. It showed good oral absorption and long-lasting, dose-dependent plasma levels making it a promising compound for drug development.

Topics: Animals; Atrial Function; Cerebral Cortex; Drug Evaluation, Preclinical; Guinea Pigs; Haplorhini; Heart Atria; Histamine Antagonists; Histamine Release; Ileum; Imidazoles; In Vitro Techniques; Mice; Muscle Contraction; Muscle, Smooth; Rats; Receptors, Histamine H1; Receptors, Histamine H2; Receptors, Histamine H3; Structure-Activity Relationship; Synaptosomes

Novel derivatives of the highly potent and selective histamine H3-receptor antagonist ciproxifan (3) with different chain lengths as well as with structural variants of the cyclopropyl ketone moiety have been prepared and screened for their antagonist H3-receptor potencies in vitro and in vivo. Some derivatives (2, 6-8, 12) containing other functionalities were effective in vitro in the same (sub)nanomolar concentration range and in vivo in a remarkably low oral dose.

Topics: Animals; Cerebral Cortex; Drug Design; Histamine Antagonists; Histamine Release; Imidazoles; Molecular Structure; Rats; Receptors, Histamine H3; Structure-Activity Relationship; Synaptosomes

Starting from the sequence of the human histamine H(3) receptor (hH(3)R) cDNA, we have cloned the corresponding rat cDNA. Whereas the two deduced proteins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed distinct affinities. Thioperamide and ciproxifan were about 10 fold more potent at the rat than at the human receptor, whereas FUB 349 displayed a reverse preference. Histamine, (R)alpha-methylhistamine, proxyfan or clobenpropit were nearly equipotent at H(3) receptors of both species. The inverse discrimination patterns of ciproxifan and FUB 349 were partially changed by mutation of one amino acid (V122A), and fully abolished by mutation of two amino acids (A119T and V122A), in TM3 of the rH(3)R located in the vicinity of Asp(114) purported to salt-link the ammonium group of histamine. Therefore, these two residues appear to be responsible for the distinct pharmacology of the H(3)R in the two species.

Topics: Amino Acid Sequence; Amino Acid Substitution; Amino Acids; Animals; Binding, Competitive; COS Cells; DNA, Complementary; Dose-Response Relationship, Drug; Histamine Antagonists; Humans; Imidazoles; Membrane Proteins; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Piperidines; Protein Structure, Tertiary; Radioligand Assay; Rats; Receptors, Histamine H3; Sequence Alignment; Sequence Homology, Amino Acid; Tritium