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Holger Stark - One of the best experts on this subject based on the ideXlab platform.

  • novel pyrrolidinone derivative lacks claimed Histamine H3 Receptor stimulation in Receptor binding and functional studies
    European Journal of Medicinal Chemistry, 2020
    Co-Authors: David Reiner, Olivier Labeeuw, Marc Capet, Aleksandra Zivkovic, Stephane Krief, Holger Stark
    Abstract:

    Abstract Since the discovery and early characterization of the Histamine H3 Receptor (H3R) in the 1980′s, predominantly imidazole-based agonists were presented to the scientific community such as Nα-methylHistamine (Nα-MeHA) or (R)-α-methylHistamine ((R)α-MeHA). Whereas therapeutic applications have been prompted for H3R agonists such as treatment of pain, asthma and obesity, several drawbacks associated with imidazole-containing ligands makes the search for new agonists for this Receptor demanding. Accordingly, high interest arose after publication of several pyrrolidindione-based, highly affine H3R agonists within this journal that avoid the imidazole moiety and thus, presenting a novel type of potential pharmacophores (Ghoshal, Anirban et al., 2018). In our present study performed in two independent laboratories, we further evaluated the exposed lead-compound (EC50 = 0.1 nM) of the previous research project with regards to pharmacological behavior at H3R. Thereby, no binding affinity was observed in neither [3H]Nα-MeHA nor bodilisant displacement assays that contradicts the previously published activity. Additional functional exploration employing GTPγ[35S], cAMP-accumulation assay and cAMP response element (CRE)-driven reporter gene assays exhibited slight partial agonist properties of such pyrrolidindiones but acting apart from the reported concentration range. We conclude, that the previously reported actions of such pyrrolidindiones result from an overestimation based on the method of measurement and thus, we cast doubt on the new pharmacophores with H3R agonist activity.

  • the dual active Histamine H3 Receptor antagonist and acetylcholine esterase inhibitor e100 ameliorates stereotyped repetitive behavior and neuroinflammmation in sodium valproate induced autism in mice
    Chemico-Biological Interactions, 2019
    Co-Authors: Nermin Eissa, Dorota łazewska, Holger Stark, David Reiner, Sheikh Azimullah, Petrilla Jayaprakash, Richard L Jayaraj, Shreesh Ojha, Rami Beiram, Katarzyna Kieckononowicz
    Abstract:

    Abstract Postnatal exposure to valproic acid (VPA) in rodents induces autism-like neurobehavioral defects which are comparable to the motor and cognitive deficits observed in humans with autism spectrum disorder (ASD). Histamine H3 Receptor (H3R) and acetylcholine esterase (AChE) are involved in several cognitive disorders such as Alzheimer's disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with ASD. Therefore, the present study aimed at evaluating effect of the novel dual-active ligand E100 with high H3R antagonist affinity and balanced AChE inhibition on autistic-like repetitive behavior, anxiety parameters, locomotor activity, and neuroinflammation in a mouse model of VPA-induced ASD in C57BL/6 mice. E100 (5, 10, and 15 mg/kg) dose-dependently and significantly ameliorated repetitive and compulsive behaviors by reducing the increased percentages of nestlets shredded (all P

  • Histamine H3 Receptor antagonists inverse agonists where do they go
    Pharmacology & Therapeutics, 2019
    Co-Authors: Nakisa Ghamari, Holger Stark, Omid Zarei, Joseantonio Ariasmontano, David Reiner, Siavoush Dastmalchi, Maryam Hamzehmivehroud
    Abstract:

    Since the discovery of the Histamine H3 Receptor in 1983, tremendous advances in the pharmacological aspects of H3 Receptor antagonists/inverse agonists have been accomplished in preclinical studies. At present, there are several drug candidates that reached clinical trial studies for various indications. However, entrance of these candidates to the pharmaceutical market is not free from challenges, and a variety of difficulties is engaged with their developmental process. In this review, the potential role of H3 Receptors in the pathophysiology of various central nervous system, metabolic and allergic diseases is discussed. Thereafter, the current status for H3 Receptor antagonists/inverse agonists in ongoing clinical trial studies is reviewed and obstacles in developing these agents are emphasized.

  • Histamine H3 Receptor as a potential target for cognitive symptoms in neuropsychiatric diseases
    Behavioural Brain Research, 2016
    Co-Authors: Bassem Sadek, Ali Saad, Adel Sadeq, Fakhreya Y Jalal, Holger Stark
    Abstract:

    The potential contributions of the brain Histaminergic system in neurodegenerative diseases, and the possiblity of Histamine-targeting treatments is attracting considerable interests. The Histamine H3 Receptor (H3R) is expressed mainly in the central nervous system, and is, consequently, an attractive pharmacological target. Although recently described clinical trials have been disappointing in attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCH), numerous H3R antagonists, including pitolisant, demonstrate potential in the treatment of narcolepsy, excessive daytime sleepiness associated with cognitive impairment, epilepsy, and Alzheimer's disease (AD). This review focuses on the recent preclinical as well as clinical results that support the relevance of H3R antagonists for the treatment of cognitive symptoms in neuropsychiatric diseases, namely AD, epilepsy and SCH. The review summarizes the role of Histaminergic neurotransmission with focus on these brain disorders, as well as the effects of numerous H3R antagonists on animal models and humans.

  • Multiple Targeting Approaches on Histamine H3 Receptor Antagonists
    Frontiers in Neuroscience, 2016
    Co-Authors: Mohammad A. Khanfar, Anna Affini, Kiril Lutsenko, Katarina Nikolic, Stefania Butini, Holger Stark
    Abstract:

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional Histamine H3 Receptor antagonists has clearly increased. Since Histamine H3 Receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on Histamine H3 Receptor antagonists on different G-protein coupled Receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

X Ligneau - One of the best experts on this subject based on the ideXlab platform.

  • preclinical evaluation of the abuse potential of pitolisant a Histamine H3 Receptor inverse agonist antagonist compared with modafinil
    British Journal of Pharmacology, 2013
    Co-Authors: M Uguen, X Ligneau, Jeannemarie Lecomte, Perrin David, S Belliard, P M Beardsley, J C Schwartz
    Abstract:

    Background and Purpose Pitolisant, a Histamine H3 Receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications. Experimental Approach Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model. Key Results Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model. Conclusions and Implications No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.

  • preclinical evaluation of the abuse potential of pitolisant a Histamine H3 Receptor inverse agonist antagonist compared with modafinil
    British Journal of Pharmacology, 2013
    Co-Authors: M Uguen, X Ligneau, Jeannemarie Lecomte, S Belliard, P M Beardsley, David Perrin, J C Schwartz
    Abstract:

    Background and Purpose Pitolisant, a Histamine H3 Receptor inverse agonist/antagonist is currently under Phase III clinical trials for treatment of excessive daytime sleepiness namely in narcoleptic patients. Its drug abuse potential was investigated using in vivo models in rodents and monkeys and compared with those of Modafinil, a psychostimulant currently used in the same indications. Experimental Approach Effects of Pitolisant on dopamine release in the nucleus accumbens, on spontaneous and cocaine-induced locomotion, locomotor sensitization were monitored. It was also tested in three standard drug abuse tests i.e. conditioned place preference in rats, self-administration in monkeys and cocaine discrimination in mice as well as in a physical dependence model. Key Results Pitolisant did not elicit any significant changes in dopaminergic indices in rat nucleus accumbens whereas Modafinil increased dopamine release. In rodents, Pitolisant was without any effect on locomotion and reduced the cocaine-induced hyperlocomotion. In addition, no locomotor sensitization and no conditioned hyperlocomotion were evidenced with this compound in rats whereas significant effects were elicited by Modafinil. Finally, Pitolisant was devoid of any significant effects in the three standard drug abuse tests (including self-administration in monkeys) and in the physical dependence model. Conclusions and Implications No potential drug abuse liability for Pitolisant was evidenced in various in vivo rodent and primate models, whereas the same does not seem so clear in the case of Modafinil.

  • novel and highly potent Histamine H3 Receptor ligands part 2 exploring the cyclohexylamine based series
    Bioorganic & Medicinal Chemistry Letters, 2011
    Co-Authors: Olivier Labeeuw, X Ligneau, Jeannemarie Lecomte, Nicolas Levoin, Olivia Poupardinolivier, Thierry Calmels, Isabelle Berrebibertrand, Philippe Robert, Jeancharles Schwartz, Marc Capet
    Abstract:

    Abstract Synthesis and biological evaluation of novel and potent cyclohexylamine-based Histamine H3 Receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human Receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation.

  • potential utility of Histamine H3 Receptor antagonist pharmacophore in antipsychotics
    Bioorganic & Medicinal Chemistry Letters, 2009
    Co-Authors: Y Von Coburg, Tim Kottke, Lilia Weizel, X Ligneau
    Abstract:

    Abstract Histamine H3 Receptor (H3R) antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets we have designed typical and atypical neuroleptics with an additional Histamine H3 pharmacophore. The 4-(3-piperidinopropoxy)phenyl pharmacophore moiety has been linked to amitriptyline, maprotiline, chlorpromazine, chlorprothixene, fluphenazine, and clozapine. Amide, amine and ester elements have been used generally to maintain or slightly shift affinity at dopamine D2-like Receptors (D2 and D3), to decrease affinity at Histamine H1 Receptors, and to obtain H3R ligands with low nanomolar or subnanomolar affinity. Change of effects at D1-like Receptors (D1 and D5) were heterogeneous. With these newly profiled compounds different antipsychotic properties might be achieved.

  • fluorescent non imidazole Histamine H3 Receptor ligands with nanomolar affinities
    ChemInform, 2006
    Co-Authors: Michael Amon, X Ligneau, Jeancharles Schwartz, Holger Stark
    Abstract:

    Abstract ω-Piperidinoalkanamine derivatives with fluorescent moieties (2-cyanoisoindol-1-yl, 7-nitrobenzofurazan-4-yl) have been synthesized starting from piperidine in three steps. The compounds display moderate to good Histamine hH3 Receptor affinities with Ki values ranging from 178 to 11 nM. The new compounds may act as tools for identification and understanding of the binding site on the Histamine H3 Receptor.

Walter Schunack - One of the best experts on this subject based on the ideXlab platform.

  • influence of bulky substituents on Histamine H3 Receptor agonist antagonist properties
    Journal of Medicinal Chemistry, 2002
    Co-Authors: Astrid Sasse, X Ligneau, Walter Schunack, Jean-michel Arrang, A Rouleau, Jeancharles Schwartz, Robin C Ganellin, Holger Stark
    Abstract:

    Novel derivatives of 3-(1H-imidazol-4-yl)propanol were designed on the basis of lead compounds belonging to the carbamate or ether series possessing (partial) agonist properties on screening assays of the Histamine H3 Receptor. One pair of enantiomers in the series of α-methyl-branched chiral carbamates was stereoselectively prepared in high optical yields. Enantiomeric purity was checked by Mosher amide derivatives of precursors and capillary electrophoresis of the final compounds with trimethyl-β-cyclodextrin as chiral selector, and was determined to be ≥95%. The novel compounds were investigated in various Histamine H3 Receptor assays in vitro and in vivo. Some compounds displayed partial agonist activity on synaptosomes of rat brain cortex, whereas others exhibited antagonist properties only. Selected compounds were investigated in [125I]iodoproxyfan binding studies on the human Histamine H3 Receptor and showed high affinity in the nanomolar concentration range. Under in vivo conditions after oral adm...

  • development of a new class of nonimidazole Histamine H3 Receptor ligands with combined inhibitory Histamine n methyltransferase activity
    Journal of Medicinal Chemistry, 2002
    Co-Authors: Joachim Apelt, X Ligneau, Walter Schunack, Jean-michel Arrang, J C Schwartz, Robin C Ganellin, Heinz H Pertz, Holger Stark
    Abstract:

    In search of novel ways to enhance Histaminergic neurotransmission in the central nervous system, a new class of nonimidazole Histamine H3 Receptor ligands were developed that simultaneously posses...

  • azomethine prodrugs of r alpha methylHistamine a highly potent and selective Histamine H3 Receptor agonist
    Current Medicinal Chemistry, 2001
    Co-Authors: M Krause, Holger Stark, Walter Schunack
    Abstract:

    The Histamine H3 Receptor is considered a potential target for novel drugs as it regulates the activity of various neurotransmitters in the peripheral and the central nervous system. Particularly H3-Receptor agonists have been suggested to become valuable drugs for the treatment of several CNS disorders, inflammatory and acid related diseases. Due to its strong basicity and polarity the highly potent and selective Histamine H3-Receptor agonist (R)-alpha-methylHistamine hardly penetrates biological membranes and is furthermore rapidly inactivvated in vivo. Thus, lipophilic, non-basic azomethine prodrugs of (R)-alpha-methylHistamine have been developed to overcome its pharmacokinetic disadvantages. This bioreversible derivatization decreased its basicity, increased its lipophilicity and reduced its metabolization. As a result the biological half-life was prolonged and oral absorption as well as penetration into the brain were significantly increased. By systematic variation of the pro-moiety we were ab le to optimize the pharmacokinetic properties which allow for both peripheral and central delivery of the parent amine. The azomethine prodrugs described herein display satisfactory stability to be orally administered while being adequately labile to deliver (R)-alpha-methylHistamine at sufficient concentrations in vivo. At present, these azomethines not only serve as valuable tools for pharmacological studies related to the Histamine H3 Receptor, but also represent a promising approach to achieve therapeutic application of the Histamine H3-Receptor agonist (R)-alpha-methylHistamine.Currently the parent compound of the prodrugs is under clinical development phase II.

  • Influence of imidazole replacement in different structural classes of Histamine H3-Receptor antagonists
    European Journal of Pharmaceutical Sciences, 2001
    Co-Authors: Galina Meier, X Ligneau, C. Robin Ganellin, Jeancharles Schwartz, Joachim Apelt, Ulrich Reichert, Sven Graßmann, Fabien Leurquin, Walter Schunack
    Abstract:

    Abstract The reference compounds for Histamine H3-Receptor antagonists carry as a common feature an imidazole moiety substituted in the 4-position. Very recently novel ligands lacking an imidazole ring have been described possessing a N-containing non-aromatic heterocycle instead. In this study we investigated whether imidazole replacement, favourably by a piperidine moiety, is generally applicable to different structural classes of reference compounds, e.g., thioperamide, carboperamide, clobenpropit, FUB 181, ciproxifan, etc. While replacement led to a loss of affinity for many of the compounds, it was successfully applied to some ether derivatives. The piperidine analogues of FUB 181 and ciproxifan, 3-(4-chlorophenyl)propyl 3-piperidinopropyl ether hydrogen oxalate (6) and cyclopropyl 4-(3-piperidinopropyloxy)phenyl methanone hydrogen maleate (7), almost maintained in vitro affinities, pKi values of 7.8 and 8.4, respectively, and showed high potency in vivo after p.o. administration (ED50 values of 1.6 and 0.18 mg/kg, respectively).

  • importance of the lipophilic group in carbamates having Histamine H3 Receptor antagonist activity
    Die Pharmazie, 2000
    Co-Authors: Katarzyna Kieckononowicz, Astrid Sasse, X Ligneau, Mariusz Wiecek, C. Robin Ganellin, Walter Schunack
    Abstract:

    : In order to evaluate changes in the lipophilic part of designed carbamates concerning their potential Histamine H3-Receptor antagonist properties a new series of O-[3-(1H-imidazol-4-yl)propanol]carbamates was derived containing N-mono- or di-alkenyl, alkynyl, cycloalkyl, or double-branched alkyl substituents. The compounds were tested in vitro for their H3-Receptor antagonist activity on synaptosomes of rat cerebral cortex and shared moderate to high antagonist activity in vitro. In this series 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate (4) was the most potent compound in vitro (Ki = 6.3 nM). H3-Receptor antagonist activity in the central nervous system (CNS) was detected for most compounds in the in vivo H3-Receptor assay based upon measurement of brain N tau-methylHistamine levels after p.o. administration to mice. The most effective carbamate in vivo, 3-(1H-imidazol-4-yl)propyl N-(allyl)carbamate (3), showed higher CNS potency (ED50 = 0.48 mg/kg p.o.) than the reference antagonist thioperamide. For some novel carbamates their Histamine H1- and H2-Receptor activities were determined on isolated organs of guinea-pig thereby demonstrating their high H3-Receptor selectivity.

Hendrik Timmerman - One of the best experts on this subject based on the ideXlab platform.

  • Brain penetration of the Histamine H3 Receptor antagonists thioperamide and clobenpropit in rat and mouse, determined with ex vivo [125I]iodophenpropit binding.
    Brain research, 1996
    Co-Authors: T. Mochizuki, Rob Leurs, F P Jansen, Albert D. Windhorst, Atsushi Yamatodani, Kazutaka Maeyama, Hendrik Timmerman
    Abstract:

    We investigated the brain penetration of the Histamine H3 Receptor antagonists thioperamide and clobenpropit using ex vivo [125I]iodophenpropit binding. Homogenates of the rat cortex, striatum and mouse whole brain were prepared 1 h after subcutaneous injection of the H3 antagonists and incubated with [125I]iodophenpropit, a radiolabeled H3 Receptor antagonist, to determine the H3 Receptor occupancy. Specific [125I]iodophenpropit binding to the rat cortex and striatum was inhibited by thioperamide with IC30 values of 1.0 and 1.5 mg/kg, respectively. Clobenpropit also inhibited [125I]iodophenpropit binding, but was less potent (IC30: 18 and 19 mg/kg in the rat cortex and striatum, respectively) than thioperamide. Similar results were obtained in experiments with mouse whole brain (3.5 and 13 mg/kg for thioperamide and clobenpropit), indicating that there is no important species differences in the brain penetration of these drugs between rats and mice. These findings suggest that after peripheral injection both in rat and mouse thioperamide penetrates the blood-brain barrier more efficiently compared to clobenpropit.

  • characterization of the binding of the first selective radiolabeled Histamine H3 Receptor antagonist 125i iodophenpropit to rat brain
    British Journal of Pharmacology, 1994
    Co-Authors: Frank P Jansen, H P Voss, R C Vollinga, T. S. Wu, B. Rademaker, Aalt Bast, Harry W.m. Steinbusch, Hendrik Timmerman
    Abstract:

    1. The binding of the first selective radiolabelled Histamine H3-Receptor antagonist [125I]-iodophenpropit to rat cerebral cortex membranes was characterized. 2. [125I]-iodophenpropit, radiolabelled to a high specific activity of 1900 Ci mmol-1, saturably bound to a single class of sites with a KD of 0.57 +/- 0.16 nM (n = 4) and Bmax of 268 +/- 119 fmol mg-1 protein. 3. Specific binding at a concentration below 1 nM represented 50 to 60% of total binding. 4. Binding of [125I]-iodophenpropit to rat cerebral cortex membranes was readily displaced by Histamine H3-agonists and antagonists. In contrast, the inhibitory potencies of selective Histamine H1- and H2-Receptor ligands were very low. 5. [125I]-iodophenpropit was biphasically displaced by the Histamine H3-Receptor antagonists, burimamide and dimaprit, which may indicate the existence of Histamine H3-Receptor subtypes. Other Histamine H3-Receptor antagonists showed a monophasic displacement. 6. Competition binding curves of H3-agonists were biphasic and showed a rightward shift upon the addition of the nonhydrolysable GTP analogue, guanosine 5'-o-(3-thio) triphosphate (GTP gamma S; 100 microM) which implicates the interaction of Histamine H3-Receptors with G-proteins. The affinities of the H3-Receptor antagonists iodophenpropit, thioperamide and burimamide were not altered by GTP gamma S. 7. Histamine competition binding curves were shifted to the right by different nucleotides (100 microM) with a rank order of potency GTP gamma S > Gpp(NH)p, GTP.(ABSTRACT TRUNCATED AT 250 WORDS)

  • the first radiolabeled Histamine H3 Receptor antagonist 125i iodophenpropit saturable and reversible binding to rat cortex membranes
    European Journal of Pharmacology, 1992
    Co-Authors: Frank P Jansen, B. Rademaker, Aalt Bast, Hendrik Timmerman
    Abstract:

    Abstract We describe the binding to rat cortex membranes of [125I]iodophenpropit, the first radiolabeled Histamine H3 antagonist. The binding of [125I]iodophenpropit is selective, saturable, readily reversible, and of high affinity (KD 0.32 nM; Bmax 209 fmol/mg of protein). Specific binding at a concentration of 0.3 nM accounted for 45–55% of the total binding. [125I]Iodophenpropit seems to fulfill the criteria for a suitable ligand for Histamine H3 Receptor binding studies.

Katarzyna Kieckononowicz - One of the best experts on this subject based on the ideXlab platform.

  • the dual active Histamine H3 Receptor antagonist and acetylcholine esterase inhibitor e100 ameliorates stereotyped repetitive behavior and neuroinflammmation in sodium valproate induced autism in mice
    Chemico-Biological Interactions, 2019
    Co-Authors: Nermin Eissa, Dorota łazewska, Holger Stark, David Reiner, Sheikh Azimullah, Petrilla Jayaprakash, Richard L Jayaraj, Shreesh Ojha, Rami Beiram, Katarzyna Kieckononowicz
    Abstract:

    Abstract Postnatal exposure to valproic acid (VPA) in rodents induces autism-like neurobehavioral defects which are comparable to the motor and cognitive deficits observed in humans with autism spectrum disorder (ASD). Histamine H3 Receptor (H3R) and acetylcholine esterase (AChE) are involved in several cognitive disorders such as Alzheimer's disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with ASD. Therefore, the present study aimed at evaluating effect of the novel dual-active ligand E100 with high H3R antagonist affinity and balanced AChE inhibition on autistic-like repetitive behavior, anxiety parameters, locomotor activity, and neuroinflammation in a mouse model of VPA-induced ASD in C57BL/6 mice. E100 (5, 10, and 15 mg/kg) dose-dependently and significantly ameliorated repetitive and compulsive behaviors by reducing the increased percentages of nestlets shredded (all P

  • Histamine H3 Receptor antagonist e177 attenuates amnesia induced by dizocilpine without modulation of anxiety like behaviors in rats
    Neuropsychiatric Disease and Treatment, 2019
    Co-Authors: Alaa Alachkar, Katarzyna Kieckononowicz, Dorota łazewska, Nadia Khan, Bassem Sadek
    Abstract:

    Background: Alzheimer disease (AD) is the main cause of dementia in elderly people. The potential of Histamine H3 Receptor (H3R) antagonists as a pharmacological treatment of several neuropsychiatric diseases is well established. Methods: The novel non-imidazole-based H3R antagonist E177 was screened for its pro-cognitive effects on the inhibitory avoidance paradigm (IAP) and novel object recognition (NOR) task in a dizocilpine (DIZ)-induced model of amnesia in male Wistar rats. Donepezil, an acetylcholine esterase inhibitor, was used as the reference drug. Results: Acute systemic treatment with E177 (1.25, 2.5, 5, and 10 mg/kg intraperitoneally [i.p.]) significantly attenuated the cognitive impairments induced by DIZ in the IAP (all P-values 0.05, n=8) or the elevated plus maze test (all P-values >0.05, n=6-8), which indicated that the E177-induced enhancement of memory performance in the IAP or NOR task was unrelated to changes in emotional response or in spontaneous locomotor activity. Conclusion: The observed results suggested a possible contribution of H3Rs in the alteration of brain neurotransmitters that accompany neurodegenerative diseases, such as AD.

  • the Histamine H3 Receptor inverse agonist pitolisant reduces body weight in obese mice
    Naunyn-schmiedebergs Archives of Pharmacology, 2018
    Co-Authors: Magdalena Kotanska, Kamil Kuder, Katarzyna Szczepanska, Jacek Sapa, Katarzyna Kieckononowicz
    Abstract:

    The pharmacological profile of pitolisant, a Histamine H3 Receptor antagonist/inverse agonist, indicates that this compound might reduce body weight and metabolic disturbances. Therefore, we studied the influence of pitolisant on body weight, water and sucrose intake as well as metabolic disturbances in the high-fat and high-sugar diet-induced obesity model in mice. To induce obesity, male CD-1 mice were fed a high-fat diet consisting of 40% fat blend for 14 weeks, water and 30% sucrose solution available ad libitum. Glucose tolerance test was performed at the beginning of week 15. Insulin tolerance was tested the day after. At the end of study, plasma levels of triglycerides and cholesterol were determined. Pitolisant at dose of 10 mg/kg bw (ip) was administrated during 14 days, starting from the beginning of week 13. Metformin at dose of 100 mg/kg bw (ip) was used as reference drug. Mice fed with high-fat diet and sucrose solution showed more weight gain throughout the 12-week period of inducing obesity. Animals fed with high-fat diet and treated with pitolisant (for the next 14 days) showed significantly less weight gain than mice from the control group consuming a high-fat feed. In the group treated with pitolisant, glucose levels were significantly lower than glucose levels of control obese mice after glucose load. The plasma triglyceride levels in pitolisant-treated mice were significantly lower compared with those in control obese group. In conclusion, pitolisant has a favorable influence of body weight and improves glucose tolerance and the lipid profile in obese mice.

  • pharmacokinetics and tissue distribution of the new non imidazole Histamine H3 Receptor antagonist 1 3 4 tert butylphenoxy propyl piperidine in rats
    Xenobiotica, 2015
    Co-Authors: Malgorzata Szafarz, Katarzyna Kieckononowicz, Agata Kryczyk, Dorota Lazewska, Elzbieta Wyska
    Abstract:

    Abstract1. The aim of this study was to evaluate pharmacokinetics and tissue distribution of novel Histamine H3 Receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (compound DL76).2. Following intravenous administration of DL76 at the dose of 3 mg/kg, pharmacokinetic parameters were calculated using non-compartmental analysis. The systemic serum clearance was 10.08 L/h/kg and the estimated blood clearance was 5.64 L/h/kg. The volume of distribution at steady state was 16.1 L/kg which was greater than total body water, terminal half-life and MRT equalled 1.41 h and 1.6 h, respectively. The two-compartment pharmacokinetic model with enterohepatic circulation was also successfully fitted to the experimental data.3. After systemic administration, DL76 was rapidly distributed into all organs studied (liver, kidney, brain, and lung). The highest AUC of DL76 was observed in lungs followed by brain, where the exposure to the investigated compound expressed as AUC was almost 30 times higher than in ser...

  • new developments around Histamine H3 Receptor antagonists inverse agonists a patent review 2010 present
    Expert Opinion on Therapeutic Patents, 2014
    Co-Authors: Dorota łazewska, Katarzyna Kieckononowicz
    Abstract:

    Introduction: Histamine H3 Receptor (H3R) is involved in the central and peripheral regulation of levels of Histamine and other neurotransmitters (e.g., acetylcholine, noradrenaline, dopamine or serotonin). H3R antagonists/inverse agonists constitute attractive targets in the search for new drugs. Preclinical data indicate their potential utility in the treatment of various central nervous system (CNS), metabolic, pain and allergic disorders. So far, many structurally diverse H3R ligands have been synthesized and pharmacologically evaluated. Certain compounds have reached clinical trials. The first results from these studies have appeared. Areas covered: The literature covering patent applications (2010 through June 2013) found in the Espacenet database will be reported. Expert opinion: In comparison with previous years, recently the number of patent applications concerning H3R antagonists/inverse agonists has decreased. The utility of compounds is still being verified in pharmacological studies. The firs...