DOCSLIB.ORG

Amoxapine Inhibits the Delayed Rectifier Outward K Current

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Amoxapine Inhibits the Delayed Rectifier Outward K Current 0022-3565/10/3322-437–445$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 332, No. 2 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 159160/3553965 JPET 332:437–445, 2010 Printed in U.S.A. Amoxapine Inhibits the Delayed Rectifier Outward Kϩ Current in Mouse Cortical Neurons via cAMP/Protein Kinase A Pathways Yan-Lin He, Xiao-Qin Zhan, Guang Yang, Ji Sun, and Yan-Ai Mei Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China Received July 30, 2009; accepted November 12, 2009 Downloaded from ABSTRACT Ion channels are known to be modulated by antidepressant pine inhibition of IK. Amoxapine was also found to significantly drugs, but the molecular mechanisms are not known. We have increase intracellular cAMP levels. The effects of amoxapine on shown that the antidepressant drug amoxapine suppresses IK were abolished by preincubation with 5-hydroxytryptamine (5- ϩ rectifier outward K (IK) currents in mouse cortical neurons. At HT) and the antagonists of 5-HT2 receptor. Moreover, intracellular jpet.aspetjournals.org ␮ Ј ␥ a concentration of 10 to 500 M, amoxapine reversibly inhib- application of guanosine 5 -[ thio]-triphosphate increased IK am- ited IK in a dose-dependent manner and modulated both plitudes and prevented amoxapine-induced inhibition. The selec- steady-state activation and inactivation properties. The appli- tive Kv2.1 subunit blocker Jingzhaotoxin-III reduced IK amplitudes cation of forskolin or dibutyryl cAMP mimicked the inhibitory by 30% and also significantly abolished the inhibitory effect of effect of amoxapine on IK and abolished further inhibition by amoxapine. Together these results suggest that amoxapine inhib- amoxapine. N-[2-(p-Bromocinnamylamino)ethyl]-5-iso-quino- its IK in mouse cortical neurons by cAMP/PKA-dependent path- linesulphonamide (H-89), a protein kinase A (PKA) inhibitor, way associated with the 5-HT receptor, and suggest that the ␣ at ASPET Journals on January 16, 2020 augmented IK amplitudes and completely eliminated amoxa- Kv2.1 -subunit may be the target for this inhibition. Tricyclic antidepressants (TCAs), named after their three- kir4.1 channels in astrocytes (Su et al., 2007). Imipramine ring molecular core structure, were the first successful anti- and structurally related compounds can directly inhibit tran- depressants and have been widely used for the treatment of sient KA currents in rat hippocampal neurons, and it was depression and other psychiatric disorders (Chen et al., 2004; hypothesized that there is a specific imipramine binding site Gillman, 2007). The therapeutic effects of these drugs are consisting of an aliphatic and aromatic site on the external generally thought to be mediated by inhibition of specific side of the channel pore (Kuo, 1998). Moreover, imipramine serotonin [5-hydroxytryptamine (5-HT)] and/or norepineph- and amitriptyline can inhibit G protein-activated inwardly rine transporters in the brain (Baldessarini, 2001), whereas rectifying Kϩ channels expressed in Xenopus oocytes (Taka- the adverse side effects of TCAs have been attributed to hashi et al., 2006). In addition, TCAs have been shown to interactions with muscarinic, adrenergic, and histamine re- modulate Ca2ϩ-activated Kϩ channels and ClϪ channels ceptors (Baldessarini, 2001). In addition to these pharmaco- (Terstappen et al., 2001; Maertens et al., 2002). Moreover, logic interactions, TCAs have been reported to exert addi- TCAs are known to alleviate various pain syndromes by tional effects on diverse ion channels. Nortriptyline is reported to overlapping with the local anesthetic site in Naϩ channels be a potent blocker of voltage-gated inwardly rectifying (Song et al., 2008). Although the effects on neurotransmitter transporters are held to underlie the activity of TCAs, it is possible that their affinity for ion channels may modulate the This work was supported in part by the National Basic Research Program therapeutic effects and side effects of these molecules. of China [Grant 2007CB512303]; Shanghai Leading Academic Discipline Project [Grant B111]; and the National Talent Training Fund in Basic Re- Amoxapine is a second-generation TCA previously intro- search of China [Grant J0630643]. duced as an alternative to traditional TCAs because of its Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. shorter onset of action and reduced cardiotoxicity. The mol- doi:10.1124/jpet.109.159160. ecule was found to exert antipsychotic effects in animal mod- ABBREVIATIONS: TCA, tricyclic antidepressant; 5-HT, 5-hydroxytryptamine; IK, delayed rectifier potassium current; PKA, protein kinase A; ANOVA, analysis of variance; PBS, phosphate-buffered saline; HEK, human embryonic kidney; GTP␥S, guanosine 5Ј-[␥-thio]-triphosphate; db-cAMP, dibutyryl cAMP; H-89, N-[2-(p-bromocinnamylamino)ethyl]-5-iso-quinolinesulphonamide; 4-AP, 4-aminopyridine; C6-ceramide, dihy- droceramide C6; JZTX-III, Jingzhaotoxin-III; DMSO, dimethyl sulfoxide; IA, transient potassium current. 437 438 He et al. els (Greenblatt et al., 1978) and was tested as a single-drug actively proliferating fibroblasts for 48 h. On day 4, cultured cells treatment for psychotic depression. In systematic double- were washed and maintained in fresh medium. All the experiments blind trials, amoxapine was found to be of equal efficacy to were carried out with cortical neurons during 6 to 10 days in culture. that of an antidepressant and an antipsychotic (Anton and Patch-Clamp Recordings. Whole-cell currents of cortex neurons were recorded using a patch-clamp technique. Before I recording, Burch, 1990). A recent study found that the antipsychotic K the culture medium was replaced with a bath solution containing activity of amoxapine was comparable with that of risperi- 140 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1 mM MgCl2, and 0.001 done (Apiquian et al., 2005). Furthermore, because amoxa- mM tetrodotoxin (pH adjusted to 7.4 using NaOH). Soft glass record- pine is now off-patent and can be produced at generic prices, ing pipettes were filled with an internal solution containing 135 mM the drug could potentially rival other typical antipsychotics. potassium gluconate, 10 mM KCl, 10 mM HEPES, 1 mM CaCl2,2mM Therefore, an understanding of the molecular and cellular MgCl2, and 10 mM EGTA (pH adjusted to 7.3 using KOH). The mechanisms underlying the therapeutic effects and/or side pipette resistance is 5 to 7 M⍀ after filling with the internal solution. effects of amoxapine is not of purely academic interest. Al- All the recordings were performed at room temperature (23–25°C). though some reports have suggested that amoxapine may Data Acquisition and Analysis. All the currents were recorded using an Axopatch 200B amplifier (Axon Instruments, Sunnyvale, also target 5-HT or D2 receptors (Nasu et al., 2000), few studies have addressed the molecular mechanism that is CA) operated in voltage-clamp mode. A Pentium (Intel Corporation, responsible for the action of this molecule. Santa Clara, CA) computer connected to the recording equipment with a Digidata 1300 (MDS Analytical Technologies, Sunnyvale, CA) Kϩ channels are extremely diverse in structure and func- analog-to-digital interface. Current was digitally sampled at 100 ␮s tion and have been held to be among the most important (10 kHz). The current signals were filtered by a 3-kHz, three-pole Downloaded from signaling macromolecules both in neuronal and non-neuro- Bessel filter. Currents were corrected on-line for leak and residual ϩ nal cells. In the central nervous system, K channels’ activity capacitance transients by a P/4 protocol. Data acquisition and anal- determines the shape, frequency, and duration of action po- ysis were performed with pClamp 8.01 software (Axon Instruments) tentials (Melishchuk et al., 1998). In addition, Kϩ channels and/or Origin 6.1 (MicroCal, Northampton, MA). Statistical analysis play a major role in setting and maintaining the resting was performed using the Student’s t test with nonpaired comparison or paired comparisons where it was relevant. Values were given as membrane potential, and the modification of this potential jpet.aspetjournals.org ϩ Ϯ Ͻ can alter neuronal excitability by activating Ca2 channels mean S.E.M., with n as the number of cell tested. P value 0.05 and modulating neuronal transmitter release (Roeper and was used to denote the statistical difference between groups. When multiple comparisons were made, data were analyzed by a one-way Pongs, 1996). Indeed, blockade of Kϩ channels has been analysis of variance (ANOVA) test. proposed as a potential therapy for diverse disorders, includ- cAMP Assay. cAMP levels were measured as described previ- ing myasthenia gravis, multiple sclerosis, Huntington’s cho- ously (Clark et al., 2004). In brief, 1 ϫ 105 cells were plated in each ϩ rea, and Alzheimer’s disease. The role of K channels is 35-mm dish and grown to confluence. Cells were washed with 1 ml of underscored by the accumulation of potassium ion that takes medium and preincubated at 37°C for 10 min in the presence of the at ASPET Journals on January 16, 2020 place during repetitive neuronal firing, and anticonvulsant phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (2.5 mM) drugs modulating Kϩ channel activity have potential as a (Sigma-Aldrich, St. Louis, MO). Cells were incubated for an addi- means to control seizure activity (Liu et al., 2007). Although tional 3 min at 37°C with or without amoxapine-varying concentra- ϩ ␮ some TCAs have previously been reported to target K chan- tions of 10, 50, and 100 M. The medium was removed, and 0.5 ml of nels, few investigations have addressed the possibility that HCl (0.1 M) with 0.8% Triton X-100 (Sigma-Aldrich) was added to ϩ the plates. After 10-min incubation at room temperature, the lysate amoxapine might modify the activity of voltage-gated K was removed from the plates and centrifuged for 2 min.
Load more

Recommended publications
  • SIGHI-Leaflet Histamine Elimination Diet Simplified Histamine Elimination Diet for Histamine Intolerance (DAO Degradation Disorder)
    Version 2020-07-20 SIGHI-Leaflet Histamine Elimination Diet Simplified histamine elimination diet for histamine intolerance (DAO degradation disorder) For people with a DAO degradation disorder The compatibility is highly dependent on the in- who have to avoid histamine, other biogenic dividual sensitivity and the amount consumed. amines and DAO inhibitors in their diet. Furthermore, it is temporarily affected by stress, In case of histamine sensitivity due to mast cell hormones and many other factors. First and activation disorders (MCAD) this dietary guide- foremost, the freshness is an important cri- line is not sufficient! If no permanent symptom terion. Everybody has to find out by trial and er- relief can be achieved and maintained with this ror what he/she can tolerate in what quantities. diet, please follow the detailed list, which addi- At the beginning of the experimental diet this list tionally takes histamine liberators into consid- should be followed as consistently as possible. eration as completely as possible. It is available In a later stage, however, the diet should be here: based more on the experiences of the person www.mastzellaktivierung.info concerned rather than following any list. Mast cell activation disorders are often mistaken Always read the list of ingredients to find out for histamine intolerance. whether a food contains incompatible ingredi- ents. References: • Experience reports from among our members and readers • Various patient leaflets from doctors, clinics and hospitals • Experience of other patient organizations, bloggers, forum threads etc. • Scientific publications • Textbooks and cookbooks about histamine intolerance To avoid: ? Risky: Well tolerated: Fermented or microbially ripened Meals from res- Prefer fresh, unprocessed or little pro- products (e.g.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2010/0179214 A1 Dubé Et Al
    US 20100179214A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0179214 A1 Dubé et al. (43) Pub. Date: Jul. 15, 2010 (54) DOXEPIN TRANS ISOMERS AND SOMERC continuation-in-part of application No. 1 1/804,720, MIXTURES AND METHODS OF USING THE filed on May 18, 2007. SAME TO TREAT SLEEP DSORDERS (60) Provisional application No. 60/898,378, filed on Jan. (75) Inventors: Susan E. Dubé, Carlsbad, CA (US); 30, 2007, provisional application No. 60/801,824, Neil B. Kavey, Chappaqua, NY filed on May 19, 2006, provisional application No. (US) 60/833,319, filed on Jul 25, 2006. Correspondence Address: KNOBBE MARTENS OLSON & BEAR LLP Publication Classification 2040 MAINSTREET, FOURTEENTH FLOOR (51) Int. Cl. IRVINE, CA 92.614 (US) A63L/335 (2006.01) A6IP 25/20 (2006.01) (73) Assignee: SOMAXON PHARMACEUTICALS, INC., (52) U.S. Cl. ........................................................ S14/450 San Diego, CA (US) (21) Appl. No.: 12/535,623 (57) ABSTRACT The invention relates to use of the trans-(E) isomer or iso (22) Filed: Aug. 4, 2009 meric mixtures containing specified ratios of the trans-(E) and cis-(Z) isomers of doxepin, metabolites of doxepin, phar Related U.S. Application Data maceutically-acceptable salts of doxepin and prodrugs of the (63) Continuation-in-part of application No. 12/022,788, same; compositions containing the same, for the treatment of filed on Jan. 30, 2008, now abandoned, which is a sleep disorders US 2010/0179214 A1 Jul. 15, 2010 DOXEPIN TRANS ISOMERS AND SOMERC brings scrutiny from the Drug Enforcement Administration MIXTURES AND METHODS OF USING THE and other regulatory bodies, and requires registration and SAME TO TREAT SLEEP DSORDERS administrative controls in physicians offices.
    [Show full text]
  • THE USE of MIRTAZAPINE AS a HYPNOTIC O Uso Da Mirtazapina Como Hipnótico Francisca Magalhães Scoralicka, Einstein Francisco Camargosa, Otávio Toledo Nóbregaa
    ARTIGO ESPECIAL THE USE OF MIRTAZAPINE AS A HYPNOTIC O uso da mirtazapina como hipnótico Francisca Magalhães Scoralicka, Einstein Francisco Camargosa, Otávio Toledo Nóbregaa Prescription of approved hypnotics for insomnia decreased by more than 50%, whereas of antidepressive agents outstripped that of hypnotics. However, there is little data on their efficacy to treat insomnia, and many of these medications may be associated with known side effects. Antidepressants are associated with various effects on sleep patterns, depending on the intrinsic pharmacological properties of the active agent, such as degree of inhibition of serotonin or noradrenaline reuptake, effects on 5-HT1A and 5-HT2 receptors, action(s) at alpha-adrenoceptors, and/or histamine H1 sites. Mirtazapine is a noradrenergic and specific serotonergic antidepressive agent that acts by antagonizing alpha-2 adrenergic receptors and blocking 5-HT2 and 5-HT3 receptors. It has high affinity for histamine H1 receptors, low affinity for dopaminergic receptors, and lacks anticholinergic activity. In spite of these potential beneficial effects of mirtazapine on sleep, no placebo-controlled randomized clinical trials of ABSTRACT mirtazapine in primary insomniacs have been conducted. Mirtazapine was associated with improvements in sleep on normal sleepers and depressed patients. The most common side effects of mirtazapine, i.e. dry mouth, drowsiness, increased appetite and increased body weight, were mostly mild and transient. Considering its use in elderly people, this paper provides a revision about studies regarding mirtazapine for sleep disorders. KEYWORDS: sleep; antidepressive agents; sleep disorders; treatment� A prescrição de hipnóticos aprovados para insônia diminuiu em mais de 50%, enquanto de antidepressivos ultrapassou a dos primeiros.
    [Show full text]
  • List of Vital Essential and Necessary Drugs and Medical Sundries For
    LIST OF VITAL ESSENTIAL AND NECESSARY DRUGS AND 2015 MEDICAL SUNDRIES FOR PUBLIC HEALTH INSTITUTIONS Sixth Edition STANDARDS & REGULATION DIVISION JAMAICA List of Vital Essential and Necessary List of Drugs and Medical Sundries for Public Institutions List of Vital Essential and Necessary List of Drugs and Medical Sundries for Public Institutions CONTENTS CONTENTS Contd. Page Preface 5-6 Page Information on Hospitals and Health Centres 7 Explanatory Notes 8 Medical Sundries 69-73 Prescription Writing 9-10 Dental Supplies 74 Algorithm for Treatment of Hypertension 11-12 Radiotherapy – Diagnostic Agents 75 Algorithm for Management of Type 2 Diabetes 13-14 Raw Materials 76 List of Drugs Designated for NHF 15-17 List of Drugs Designated for JADEP 18 VOLUME11 – SPECIALIST LIST 77 VOLUME 1 – GENERAL LIST 19 CLASSIFICATION OF DRUGS SECTION 1. Cardiovascular System 78 CLASSIFICATION OF DRUGS SECTION 2. Central Nervous System 79 SECTION 1. Cardiovascular System 20-24 SECTION 3. Dermatology 80 SECTION 2. Central Nervous System 25-30 SECTION 4. Endocrine System 80 SECTION 3. Dermatology 31-33 SECTION 5. Gastro-intestinal System 81 SECTION 4. Ear, Nose and Oropharynx 34-35 SECTION 6. Infections 81 SECTION 5. Endocrine System 36-38 SECTION 7. Malignant Disease and SECTION 6. Gastro-intestinal System 39-40 Immunosuppression 82 SECTION 7. Infections 41-46 SECTION 8. Musculoskeletal and Joint Diseases 83 SECTION 8. Malignant Disease and SECTION 9. Ophthalmology 83 Immunosuppression 47-49 SECTION 10. Genito-Urinary Tract Disorders 84 SECTION 9. Musculoskeletal and Joint Diseases 50-51 SECTION 11. Respiratory System 84 SECTION 10. Nutrition and Blood 52-54 SECTION 12.
    [Show full text]
  • Copyrighted Material
    Index Note: page numbers in italics refer to figures; those in bold to tables or boxes. abacavir 686 tolerability 536–537 children and adolescents 461 acamprosate vascular dementia 549 haematological 798, 805–807 alcohol dependence 397, 397, 402–403 see also donepezil; galantamine; hepatic impairment 636 eating disorders 669 rivastigmine HIV infection 680 re‐starting after non‐adherence 795 acetylcysteine (N‐acetylcysteine) learning disability 700 ACE inhibitors see angiotensin‐converting autism spectrum disorders 505 medication adherence and 788, 790 enzyme inhibitors obsessive compulsive disorder 364 Naranjo probability scale 811, 812 acetaldehyde 753 refractory schizophrenia 163 older people 525 acetaminophen, in dementia 564, 571 acetyl‐L‐carnitine 159 psychiatric see psychiatric adverse effects acetylcholinesterase (AChE) 529 activated partial thromboplastin time 805 renal impairment 647 acetylcholinesterase (AChE) acute intoxication see intoxication, acute see also teratogenicity inhibitors 529–543, 530–531 acute kidney injury 647 affective disorders adverse effects 537–538, 539 acutely disturbed behaviour 54–64 caffeine consumption 762 Alzheimer’s disease 529–543, 544, 576 intoxication with street drugs 56, 450 non‐psychotropics causing 808, atrial fibrillation 720 rapid tranquillisation 54–59 809, 810 clinical guidelines 544, 551, 551 acute mania see mania, acute stupor 107, 108, 109 combination therapy 536 addictions 385–457 see also bipolar disorder; depression; delirium 675 S‐adenosyl‐l‐methionine 275 mania dosing 535 ADHD
    [Show full text]
  • A Phase 3, Multicenter, Randomized, Double-Blind
    Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Treatment NCT Number: NCT03999918 Document Date: 21 Jun 2020 CLINICAL STUDY PROTOCOL UNMASKED PROTOCOL A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Treatment Protocol Number: ACP-103-054 Amendment 4 EudraCT Number: 2018-003251-37 Original Protocol Date: 30 August 2018 Protocol Amendment 1 Date: 05 December 2018 Protocol Amendment 2 Date: 18 March 2019 Protocol Amendment 3 Date: 29 October 2019 Protocol Amendment 4 Date: 21 June 2020 Confidentiality Statement This protocol is the confidential information of ACADIA Pharmaceuticals Inc. and is intended solely for the guidance of the clinical investigation. This protocol may not be disclosed to parties not associated with the clinical investigation or used for any purpose without the prior written consent of ACADIA Pharmaceuticals Inc. Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. Page 1 of 81 Study: ACP-103-054 Final Version: 1.0 Clinical Study Protocol Amendment 4 UNMASKED VERSION Date: 21 June 2020 SPONSOR SIGNATURE PAGE Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Treatment ACADIA President: President ACADIA Pharmaceuticals Inc. See appended electronic signature page Signature Date ACADIA Study Lead: Executive Director, Clinical Research ACADIA Pharmaceuticals Inc.
    [Show full text]
  • Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans
    molecules Review Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans Paul Cumming 1,2,* , Milan Scheidegger 3 , Dario Dornbierer 3, Mikael Palner 4,5,6 , Boris B. Quednow 3,7 and Chantal Martin-Soelch 8 1 Department of Nuclear Medicine, Bern University Hospital, CH-3010 Bern, Switzerland 2 School of Psychology and Counselling, Queensland University of Technology, Brisbane 4059, Australia 3 Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, CH-8032 Zurich, Switzerland; [email protected] (M.S.); [email protected] (D.D.); [email protected] (B.B.Q.) 4 Odense Department of Clinical Research, University of Southern Denmark, DK-5000 Odense, Denmark; [email protected] 5 Department of Nuclear Medicine, Odense University Hospital, DK-5000 Odense, Denmark 6 Neurobiology Research Unit, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark 7 Neuroscience Center Zurich, University of Zurich and Swiss Federal Institute of Technology Zurich, CH-8058 Zurich, Switzerland 8 Department of Psychology, University of Fribourg, CH-1700 Fribourg, Switzerland; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Hallucinogens are a loosely defined group of compounds including LSD, N,N- dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), Citation: Cumming, P.; Scheidegger, which can evoke intense visual and emotional experiences. We are witnessing a renaissance of re- M.; Dornbierer, D.; Palner, M.; search interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. Quednow, B.B.; Martin-Soelch, C. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and Molecular and Functional Imaging ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or Studies of Psychedelic Drug Action in single photon emission computer tomography (SPECT).
    [Show full text]
  • Histamine and Antihistamines Sites of Action Conditions Which Cause Release Aron H
    Learning Objectives I Histamine Pharmacological effects Histamine and Antihistamines Sites of action Conditions which cause release Aron H. Lichtman, Ph.D. Diagnostic uses Associate Professor II Antihistamines acting at the H1 and H2 receptor Pharmacology and Toxicology Pharmacological effects Mechanisms of action Therapeutic uses Side effects and drug interactions Be familiar with the existence of the H3 receptor III Be able to describe the main mechanism of action of cromolyn sodium and its clinical uses Histamine Pharmacology First autacoid to be discovered. (Greek: autos=self; Histamine Formation akos=cure) Synthesized in 1907 Synthesized in mammalian tissues by Demonstrated to be a natural constituent of decarboxylation of the amino acid l-histidine mammalian tissues (1927) Involved in inflammatory and anaphylactic reactions. Local application causes swelling redness, and edema, mimicking a mild inflammatory reaction. Large systemic doses leads to profound vascular changes similar to those seen after shock or anaphylactic origin Histamine Stored in complex with: Heparin Chondroitin Sulfate Eosinophilic Chemotactic Factor Neutrophilic Chemotactic Factor Proteases 1 Conditions That Release Histamine 1. Tissue injury: Any physical or chemical agent that injures tissue, skin or mucosa are particularly sensitive to injury and will cause the immediate release of histamine from mast cells. 2. Allergic reactions: exposure of an antigen to a previously sensitized (exposed) subject can immediately trigger allergic reactions. If sensitized by IgE antibodies attached to their surface membranes will degranulate when exposed to the appropriate antigen and release histamine, ATP and other mediators. 3. Drugs and other foreign compounds: morphine, dextran, antimalarial drugs, dyes, antibiotic bases, alkaloids, amides, quaternary ammonium compounds, enzymes (phospholipase C).
    [Show full text]
  • Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor
    pharmaceuticals Review Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor Qing Wang 1,2 , Yu Zhou 2 , Jianhui Huang 1 and Niu Huang 2,3,* 1 School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; [email protected] (Q.W.); [email protected] (J.H.) 2 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; [email protected] 3 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China * Correspondence: [email protected]; Tel.: +86-10-80720645 Abstract: Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas. Keywords: GPCR; 5-HT2BR; biased signaling; agonist; antagonist Citation: Wang, Q.; Zhou, Y.; Huang, J.; Huang, N. Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor. 1. Introduction Pharmaceuticals 2021, 14, 76.
    [Show full text]
  • Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders
    Neuropsychopharmacology (2003) 28, 402–412 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders ,1 2 3 2 Gerard J Marek* , Linda L Carpenter , Christopher J McDougle and Lawrence H Price 1Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; 2Department of Psychiatry and Human, Brown Medical School, Mood 3 Disorders Program, Behavior, Butler Hospital, Providence, RI, USA; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA Recently, the addition of drugs with prominent 5-HT2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive–compulsive disorder (OCD). These 5-HT antagonists may also be effective in 2 ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT2A receptors. These findings suggest that the simultaneous blockade of 5-HT2A receptors and activation of an unknown constellation of other 5-HT receptors indirectly as a result of 5-HT uptake inhibition might have greater therapeutic efficacy than either action alone. Animal studies have suggested that activation of 5-HT1A and 5-HT2C receptors may counteract the effects of activating 5-HT2A receptors. Additional 5-HT receptors, such as the 5-HT1B/1D/5/7 receptors, may similarly counteract the effects of 5-HT receptor activation. These clinical and preclinical observations suggest that the combination of highly 2A selective 5-HT antagonists and SSRIs, as well as strategies to combine high-potency 5-HT receptor and 5-HT transporter blockade in 2A 2A a single compound, offer the potential for therapeutic advances in a number of neuropsychiatric disorders.
    [Show full text]
  • Assessment Report
    19 September 2013 EMA/737723/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report ABILIFY MAINTENA International non-proprietary name: ARIPIPRAZOLE Procedure No. EMEA/H/C/002755/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Table of contents 1.1. Submission of the dossier .................................................................................... 6 1.2. Manufacturers ................................................................................................... 6 1.3. Steps taken for the assessment of the product ....................................................... 7 2. Scientific discussion ................................................................................ 7 2.1. Introduction ...................................................................................................... 7 2.2. Quality aspects .................................................................................................. 9 2.2.1. Introduction ................................................................................................... 9 2.2.2. Active Substance ..........................................................................................
    [Show full text]
  • Histamine, Metabolic Remodelling and Angiogenesis: a Systems Level Approach †
    biomolecules Review Histamine, Metabolic Remodelling and Angiogenesis: A Systems Level Approach † Aurelio A. Moya-García 1,2,‡ , Almudena Pino-Ángeles 3,4,‡, Francisca Sánchez-Jiménez 5,§, José Luis Urdiales 1,2,5,* and Miguel Ángel Medina 1,2,5 1 Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, 29071 Málaga, Spain; [email protected] (A.A.M.-G.); [email protected] (M.Á.M.) 2 Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain 3 Unidad de Lípidos y Arteriosclerosis, Servicio de Medicina Interna, Hospital Universitario Reina Sofia, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; [email protected] 4 Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 14004 Córdoba, Spain 5 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 29010 Málaga, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-9521-37285 † To Professor Rafael Peñafiel, in memoriam. ‡ These authors contributed equally to this work. § Retired; formerly as in affiliations 1 and 2. Abstract: Histamine is a highly pleiotropic biogenic amine involved in key physiological processes including neurotransmission, immune response, nutrition, and cell growth and differentiation. Its effects, sometimes contradictory, are mediated by at least four different G-protein coupled receptors, Citation: Moya-García, A.A.; which expression and signalling pathways are tissue-specific. Histamine metabolism conforms a Pino-Ángeles, A.; Sánchez-Jiménez, F.; Urdiales, J.L.; Medina, M.Á. very complex network that connect many metabolic processes important for homeostasis, including Histamine, Metabolic Remodelling nitrogen and energy metabolism.
    [Show full text]