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Holger Stark - One of the best experts on this subject based on the ideXlab platform.
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histamine H3 Receptor Antagonists inverse agonists where do they go
Pharmacology & Therapeutics, 2019Co-Authors: Nakisa Ghamari, Holger Stark, Omid Zarei, Joseantonio Ariasmontano, David Reiner, Siavoush Dastmalchi, Maryam HamzehmivehroudAbstract: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.
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Multiple Targeting Approaches on Histamine H3 Receptor Antagonists
Frontiers in Neuroscience, 2016Co-Authors: Mohammad A. Khanfar, Anna Affini, Kiril Lutsenko, Katarina Nikolic, Stefania Butini, Holger StarkAbstract: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.
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anticonvulsive effect of nonimidazole histamine H3 Receptor Antagonists
Behavioural Pharmacology, 2014Co-Authors: Bassem Sadek, Dorota łazewska, Holger Stark, Kamil Kuder, Dhanasekaran Subramanian, Mohamed Shafiullah, Abdu Adem, Katarzyna KieckononowiczAbstract:To determine the potential of histamine H3 Receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1–12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity
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scaffold variations in amine warhead of histamine H3 Receptor Antagonists
Drug Discovery Today: Technologies, 2013Co-Authors: Kerstin Wingen, Holger StarkAbstract:The histamine H₃ Receptor (H₃R) is involved in numerous regulatory neurotransmission processes and there-fore, is a prominent target for centrally occurring disease with some promising clinical candidates. Previous research resulted in the identification of a core pharmacophore blueprint for H₃R Antagonists/inverse agonists, which when inserted in a molecule, mostly ensures acceptable affinity. Nevertheless, variations of scaffold and peripheral areas can increase potency and pharmacokinetic profile of drug candidates. The variations in amine scaffolds of Antagonists for this aminergic GPCR are of special importance.
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azole derivatives as histamine H3 Receptor Antagonists part 2 c c and c s coupled heterocycles
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Miriam Walter, X Ligneau, Tim Kottke, J C Schwartz, Kathleen Isensee, Jeanclaude Camelin, Holger StarkAbstract:With a small series of compounds we demonstrated the variability in the core region of the human histamine H(3) Receptor (hH(3)R) antagonist structural blueprint by introducing polar azole groups (oxazole, oxadiazole, thiazole and triazole). Additional variations achieved by coupling different residues to the heterocyclic core structure led to further optimisation of in vitro Receptor binding of the novel azole derivatives.
Walter Schunack - One of the best experts on this subject based on the ideXlab platform.
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refined docking as a valuable tool for lead optimization application to histamine H3 Receptor Antagonists
Archiv Der Pharmazie, 2008Co-Authors: Nicolas Levoin, Walter Schunack, Robin C Ganellin, Thierry Calmels, Olivia Poupardinolivier, Olivier Labeeuw, Denis Danvy, Philippe Robert, Isabelle Berrebibertrand, Holger StarkAbstract:Drug-discovery projects frequently employ structure-based information through protein modeling and ligand docking, and there is a plethora of reports relating successful use of them in virtual screening. Hit/lead optimization, which represents the next step and the longest for the medicinal chemist, is very rarely considered. This is not surprising because lead optimization is a much more complex task. Here, a homology model of the histamine H(3) Receptor was built and tested for its ability to discriminate ligands above a defined threshold of affinity. In addition, drug safety is also evaluated during lead optimization, and "antitargets" are studied. So, we have used the same benchmarking procedure with the HERG channel and CYP2D6 enzyme, for which a minimal affinity is strongly desired. For targets and antitargets, we report here an accuracy as high as at least 70%, for ligands being classified above or below the chosen threshold. Such a good result is beyond what could have been predicted, especially, since our test conditions were particularly stringent. First, we measured the accuracy by means of AUC of ROC plots, i. e. considering both false positive and false negatives. Second, we used as datasets extensive chemical libraries (nearly a thousand ligands for H(3)). All molecules considered were true H(3) Receptor ligands with moderate to high affinity (from microM to nM range). Third, the database is issued from concrete SAR (Bioprojet H(3) BF2.649 library) and is not simply constituted by few active ligands buried in a chemical catalogue.
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Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 Receptor Antagonists.
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Dorota Łażewska, X Ligneau, Walter Schunack, Jean-charles Schwartz, Holger Stark, Katarzyna Kieć-kononowiczAbstract:A series of aliphatic and aromatic ether derivatives of 3-piperidinopropan-1-ol has been prepared by four different methods. The ethers obtained were evaluated for their affinities at recombinant human histamine H3 Receptor, stably expressed in CHO-K1 or HEK 293 cells. All compounds investigated show from moderate to high in vitro affinities in the nanomolar concentration range. Selected compounds were investigated under in vivo conditions after oral administration to mice. Some proved to be highly potent and orally available histamine H3 Receptor Antagonists. The most potent Antagonists in this series have been in vitro the 4-(1,1-dimethylpropyl)phenyl ether 19 (hH3R Ki = 8.4 nM) and in vivo the simple ethyl ether 2 (ED50 = 1.0 mg/kg).
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medicinal chemical and pharmacological aspects of imidazole containing histamine H3 Receptor Antagonists
Mini-reviews in Medicinal Chemistry, 2004Co-Authors: Holger Stark, Walter Schunack, Eberhard Schlicker, M Kathmann, Birgit Schlegel, Wolfgang SipplAbstract:The first Antagonists known for the histamine H3 Receptor were mono-substituted imidazole-containing compounds like thioperamide. Meanwhile numerous novel leads have been developed possessing improved affinities, selectivities, specificities, and pharmacokinetic properties. Scope and limitations of this promising class are discussed concerning their structure-activity relationships as well as pharmacological and potential therapeutic aspects.
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structural variations of 1 4 phenoxymethyl benzyl piperidines as nonimidazole histamine H3 Receptor Antagonists
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Tibor Miko, X Ligneau, Walter Schunack, Jean-michel Arrang, Jean-charles Schwartz, Heinz H. Pertz, Robin C Ganellin, Holger StarkAbstract:Abstract Recent bioisoteric replacements in histamine H 3 Receptor ligands with an exchange of the imidazole moiety by a piperidino group as well as of the trimethylene chain in 4-((3-phenoxy)propyl)-l H -imidazole derivatives (proxifan class) by an α,α ′ -xylendiyl linker represents the starting point in the development of 1-(4-(phenoxymethyl)benzyl)piperidines as a new class of nonimidazole histamine H 3 Receptor Antagonists. According to different strategies in optimization of imidazole-containing Antagonists the central benzyl phenyl ether moiety was replaced by numerous other polar functionalities. Additionally, the ortho - and meta -analogues of the lead were synthesized to determine the influence of the position of the piperidinomethyl substituent. The new compounds were tested in an in vitro binding assay for their affinities for cloned human H 3 Receptors stably expressed in CHO-K1 cells and for their oral in vivo potencies brain in a functional screening assay in the brain of mice. Additionally, activities of selected compounds were determined in the guinea-pig ileum functional test model. In contrast to the analogues ortho -substituted compounds all other compounds maintained respectable affinities for the human H 3 Receptor (−log K i values 6.3–7.5). Despite the results from other classes of compounds the 4-methyl substituted derivatives generally displayed higher affinities than the corresponding 4-chloro substituted compounds. In vivo only the inverse phenyl benzyl ether ( 3 ) showed worthwhile antagonist potencies.
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Novel nonimidazole histamine H3 Receptor Antagonists: 1-(4-(phenoxymethyl)benzyl)piperidines and related compounds.
Journal of Medicinal Chemistry, 2003Co-Authors: Tibor Miko, X Ligneau, Walter Schunack, Jean-michel Arrang, C. Robin Ganellin, Jean-charles Schwartz, Heinz H. Pertz, Holger StarkAbstract:In an extension of very recently published studies on successful imidazole replacements in some series of histamine H3 Receptor Antagonists, we report on a new class of lipophilic nonimidazole anta...
Timothy A Esbenshade - One of the best experts on this subject based on the ideXlab platform.
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assessment of the abuse liability of abt 288 a novel histamine H3 Receptor antagonist
Psychopharmacology, 2013Co-Authors: Thomas J Hudzik, Timothy A Esbenshade, Kaitlin E Browman, Ana M Basso, Janel M Boycerustay, William Bracken, Karla Drescher, Lise I Loberg, James J. Lynch, Jorge D. BrioniAbstract:Rationale Histamine H3 Receptor Antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H3 Antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse.
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use of the H3 Receptor antagonist radioligand 3h a 349821 to reveal in vivo Receptor occupancy of cognition enhancing H3 Receptor Antagonists
British Journal of Pharmacology, 2009Co-Authors: Thomas R Miller, Kaitlin E Browman, Marlon D Cowart, Jürgen Bauch, Bruce W Surber, Jorge D. Brioni, Ivan Milicic, Kennan C. Marsh, J. Du, Timothy A EsbenshadeAbstract:BACKGROUND AND PURPOSE: The histamine H3 Receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo Receptor occupancy by H3 Receptor Antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 Receptor occupancy to blood levels and efficacy in preclinical models. EXPERIMENTAL APPROACH: In vivo cerebral cortical H3 Receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 Receptors. Comparisons were made to relate antagonist H3 Receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups. KEY RESULTS: In adult rats, [3H]-A-349821, 1.5 microg x kg(-1), penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 Receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 Receptor Antagonists inhibited H3 Receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the Antagonists corresponding to H3 Receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response. CONCLUSIONS AND IMPLICATIONS: When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 Receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 Receptor Antagonists.
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the histamine H3 Receptor an attractive target for the treatment of cognitive disorders
British Journal of Pharmacology, 2008Co-Authors: Timothy A Esbenshade, Marina I Strakhova, Robert S Bitner, Kaitlin E Browman, Marlon D Cowart, Jorge D. BrioniAbstract:The histamine H3 Receptor, first described in 1983 as a histamine autoReceptor and later shown to also function as a heteroReceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H3 Receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H3 Antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H3 Receptors by selective H3 Receptor Antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H3 Antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H3 Receptor Antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H3 Receptor antagonist has been reported to date. The discovery of effective H3 Antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H3 Receptor.
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in vitro sar of pyrrolidine containing histamine H3 Receptor Antagonists trends across multiple chemical series
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Diana L Nersesian, Timothy A Esbenshade, Thomas R Miller, Arthur A Hancock, Lawrence A Black, Timothy Vortherms, Marlon D CowartAbstract:Abstract Structure–activity relationships (SAR) were analyzed within a library of diverse yet simple compounds prepared as histamine H3 Antagonists. The libraries were constructed with a variety of low molecular weight pyrrolidines, selected from (R)-2-methylpyrrolidine, (S)-2-methylpyrrolidine, and pyrrolidine.
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Histamine H3 Receptor Antagonists: preclinical promise for treating obesity and cognitive disorders.
Molecular Interventions, 2006Co-Authors: Timothy A Esbenshade, Marlon D CowartAbstract:: The histamine H3 Receptor is an attractive G protein-coupled Receptor drug target that regulates neurotransmission in the central nervous system and plays a role in cognitive and homeostatic functions. Drug discovery efforts by numerous pharmaceutical companies have focused on the preclinical development of H3 Receptor Antagonists for the potential treatment of attention-deficit hyperactivity disorder, dementias, schizophrenia, as well as obesity and sleep disorders. This Receptor exhibits molecular, pharmacological, and functional heterogeneity that informs the preclinical development of effective Antagonists. Herein, we describe the biological and chemical implications for developing H3 Receptor Antagonists and their therapeutic potential as disclosed through animal models of cognition, sleep, and obesity.
X Ligneau - One of the best experts on this subject based on the ideXlab platform.
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azole derivatives as histamine H3 Receptor Antagonists part 2 c c and c s coupled heterocycles
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Miriam Walter, X Ligneau, Tim Kottke, J C Schwartz, Kathleen Isensee, Jeanclaude Camelin, Holger StarkAbstract:With a small series of compounds we demonstrated the variability in the core region of the human histamine H(3) Receptor (hH(3)R) antagonist structural blueprint by introducing polar azole groups (oxazole, oxadiazole, thiazole and triazole). Additional variations achieved by coupling different residues to the heterocyclic core structure led to further optimisation of in vitro Receptor binding of the novel azole derivatives.
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fluorinated non imidazole histamine H3 Receptor Antagonists
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Kathleen Isensee, X Ligneau, J C Schwartz, Michael Amon, A Galaparti, Jeanclaude Camelin, Marc Capet, Holger StarkAbstract:Abstract Fluorine substituents have become a widespread and important component in drug design and development. Here, the synthesis of fluorine containing compounds and some corresponding precursor molecules are presented for potential isotope labelling as well as their data obtained with in vitro and in vivo screenings. The compounds vary in the basic centres (piperidine or pyrrolidine) and are fluoro substituted in different positions of the basic alicyclic moiety. Pharmacological evaluation resulted in ligands with high affinities at hH3 Receptor in the nanomolar and subnanomolar concentration range and some with high antagonist in vivo potencies.
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Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 Receptor Antagonists.
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Dorota Łażewska, X Ligneau, Walter Schunack, Jean-charles Schwartz, Holger Stark, Katarzyna Kieć-kononowiczAbstract:A series of aliphatic and aromatic ether derivatives of 3-piperidinopropan-1-ol has been prepared by four different methods. The ethers obtained were evaluated for their affinities at recombinant human histamine H3 Receptor, stably expressed in CHO-K1 or HEK 293 cells. All compounds investigated show from moderate to high in vitro affinities in the nanomolar concentration range. Selected compounds were investigated under in vivo conditions after oral administration to mice. Some proved to be highly potent and orally available histamine H3 Receptor Antagonists. The most potent Antagonists in this series have been in vitro the 4-(1,1-dimethylpropyl)phenyl ether 19 (hH3R Ki = 8.4 nM) and in vivo the simple ethyl ether 2 (ED50 = 1.0 mg/kg).
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structural variations of 1 4 phenoxymethyl benzyl piperidines as nonimidazole histamine H3 Receptor Antagonists
Bioorganic & Medicinal Chemistry, 2004Co-Authors: Tibor Miko, X Ligneau, Walter Schunack, Jean-michel Arrang, Jean-charles Schwartz, Heinz H. Pertz, Robin C Ganellin, Holger StarkAbstract:Abstract Recent bioisoteric replacements in histamine H 3 Receptor ligands with an exchange of the imidazole moiety by a piperidino group as well as of the trimethylene chain in 4-((3-phenoxy)propyl)-l H -imidazole derivatives (proxifan class) by an α,α ′ -xylendiyl linker represents the starting point in the development of 1-(4-(phenoxymethyl)benzyl)piperidines as a new class of nonimidazole histamine H 3 Receptor Antagonists. According to different strategies in optimization of imidazole-containing Antagonists the central benzyl phenyl ether moiety was replaced by numerous other polar functionalities. Additionally, the ortho - and meta -analogues of the lead were synthesized to determine the influence of the position of the piperidinomethyl substituent. The new compounds were tested in an in vitro binding assay for their affinities for cloned human H 3 Receptors stably expressed in CHO-K1 cells and for their oral in vivo potencies brain in a functional screening assay in the brain of mice. Additionally, activities of selected compounds were determined in the guinea-pig ileum functional test model. In contrast to the analogues ortho -substituted compounds all other compounds maintained respectable affinities for the human H 3 Receptor (−log K i values 6.3–7.5). Despite the results from other classes of compounds the 4-methyl substituted derivatives generally displayed higher affinities than the corresponding 4-chloro substituted compounds. In vivo only the inverse phenyl benzyl ether ( 3 ) showed worthwhile antagonist potencies.
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Novel nonimidazole histamine H3 Receptor Antagonists: 1-(4-(phenoxymethyl)benzyl)piperidines and related compounds.
Journal of Medicinal Chemistry, 2003Co-Authors: Tibor Miko, X Ligneau, Walter Schunack, Jean-michel Arrang, C. Robin Ganellin, Jean-charles Schwartz, Heinz H. Pertz, Holger StarkAbstract:In an extension of very recently published studies on successful imidazole replacements in some series of histamine H3 Receptor Antagonists, we report on a new class of lipophilic nonimidazole anta...
Nicholas I Carruthers - One of the best experts on this subject based on the ideXlab platform.
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Novel benzamide-based histamine H3 Receptor Antagonists: the identification of two candidates for clinical development.
ACS Medicinal Chemistry Letters, 2015Co-Authors: Michael A Letavic, Leah Aluisio, Pascal Bonaventure, Nicholas I Carruthers, Richard Apodaca, Ann J. Barbier, Christine Dugovic, Manoj Bajpai, Anne Bonneville, Ian C FraserAbstract:The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 Receptor Antagonists is described. The compounds described are high affinity histamine H3 Antagonists. Optimization of the physical properties of these histamine H3 Antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
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Pre-clinical characterization of aryloxypyridine amides as histamine H3 Receptor Antagonists: identification of candidates for clinical development.
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Michael A Letavic, Leah Aluisio, Pascal Bonaventure, Ian C Fraser, Nicholas I Carruthers, John R. Atack, Christine Dugovic, Anita M. Everson, Mark A. Feinstein, Kenway HoeyAbstract:The pre-clinical characterization of novel aryloxypyridine amides that are histamine H3 Receptor Antagonists is described. These compounds are high affinity histamine H3 ligands that penetrate the CNS and occupy the histamine H3 Receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
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lead identification of acetylcholinesterase inhibitors histamine H3 Receptor Antagonists from molecular modeling
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Scott D Bembenek, Leah Aluisio, Kirsten L Miller, Lisa Dvorak, Timothy W Lovenberg, Richard Apodaca, Ann J. Barbier, Michael A Letavic, John M Keith, Nicholas I CarruthersAbstract:Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) Receptor antagonist. Both histamine H(3) Receptor Antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) Receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
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aplysamine 1 and related analogs as histamine H3 Receptor Antagonists
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Devin M Swanson, Sandy J Wilson, Jamin D Boggs, Timothy W Lovenberg, Richard Apodaca, Wei Xiao, Ann J. Barbier, Nicholas I CarruthersAbstract:Aplysamine-1 (1), a marine natural product, was synthesized and screened for in vitro activity at the human and rat histamine H3 Receptors. Aplysamine-1 (1) was found to possess a high binding affinity for the human H3 Receptor (Ki = 30+/-4 nM). Synthetic analogs of 1, including des-bromoaplysamine-1 (10) and dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-ethyl}-amine (13), were potent H3 Antagonists.
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A new class of diamine-based human histamine H3 Receptor Antagonists: 4-(aminoalkoxy)benzylamines.
Journal of Medicinal Chemistry, 2003Co-Authors: Richard Apodaca, Sandy J Wilson, Jamin D Boggs, Timothy W Lovenberg, Curt A. Dvorak, Wei Xiao, Ann J. Barbier, Nicholas I CarruthersAbstract:4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H3 Receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be Antagonists in a cell-based model of human histamine H3 Receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H3 Receptor antagonist.
