DOCSLIB.ORG

PET Measurements of Neuroreceptor Occupancy by Typical and Atypical Neuroleptics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PET Measurements of Neuroreceptor Occupancy by Typical and Atypical Neuroleptics 7. KuhI DE, Metter EJ, Riege WH. Patterns of local cerebral glucose utilization measurement oflocal cerebral glucose utilization: theory, procedure and normal values determined in Parkinson's disease by the [@0F]fluorodeoxyglucose method. Ann Neurol in the conscious and anesthetized albino rat. J Neurochem l977;28:897—9l6. l984;l5:4l9—424. 27. Reivich M, Alavi A, Wolf A, et al. Glucose metabolic rate kinetic model parameter 8. KuhI DE, Metier EJ, Riege WH, Markham CH. Pattems of local cerebral glucose determination in humans: the lumped constants and rate constants for [‘8F]fluorode utilization in Parkinson's disease and Huntington's disease. Ann Neurol 1984; oxyglucose and [‘‘Cjdeoxyglucose.J Cereb Blood Flow Metab l985;5: 179—192. l5(suppl):5l19—5125. 28. Foster NL, Gilman 5, Berent 5, et al. Cerebralhypometabolism in progressive supranuclear 9. Peppard RF, Martin WR, Carr GD, et al. Cerebral glucose metabolism in Parkinson's palsy studied with positron emission tomography. Ann Neurol l98824:399-406. disease with and without dementia. Arch Neurol l992;49:l262—1268. 29. Gilman S, Junck L, Markel DS, et al. Cerebral glucose hypermetabolism in Friedreich's 10. KuhI DE, Metter EJ, Benson DF, Ctal. 5imilarities of cerebral glucose metabolism in ataxia detected with positron emission tomography. Ann Neurol l990;28:750—757. Alzheimer's and Parkinsonian dementia. J Cereb Blood Flow Metab l985;5(suppl 30. Oilman 5, Markel DS, Koeppe RA, et al. Cerebellar and brainstem hypometabolism in l):5169—5170. olivopontocerebellar atrophy detected with positron emission tomography. Ann Neurol 11. Eidelberg D, Moeller JR. Dhawan V, et al. The metabolic anatomy of Parkinson's l988;23:223—230. disease: complementary [18F]fluorodeoxyglucose and [‘8F]fluorodopapositron emis 31. Heiss W-D, Pawlik 0, Herholz K, et al. Regional kinetic constants and cerebral sion tomography studies. Mov Disord l990;5:203—213. metabolic rate for glucose in normal human volunteers determined by dynamic 12. Eidelberg D, Takikawa 5, Moeller JR. et al. Striatal hypometabolism distinguishes positron emission tomography of (‘8F]-2-fluoro-2-deoxy-D-glucose. J Cereb Blood striatonigral degeneration from Parkinson's disease. Ann Neurol 1993;33:518—527. Flow Metab 1984;4:212—223. 13. Phelps ME, Huang SC, Hoffman EJ, et al. Tomographic measurements of local 32. Halliday GM, Li YW, Blumbergs PC, et al. Neuropathology of immunohistologically cerebral glucose metabolic rate in humans with [‘8F]2-fluoro--2-deoxy-D-glucose: identified brainstem neurons in Parkinson's disease. Ann Neurol 1990;27:373—385. validation of the method. Ann Neurol I979;6:37l—388. 33. Otsuka M, Ichiya Y, Hosokawa 5, et al. Striatal blood flow, glucose metabolism and 14. Hawkins RA, Phelps ME, Huang 5-C, KuhI DE. Effect of ischemia on quantification [‘8F]-DOPAuptake: difference in Parkinson's disease and atypical parkinsonism. of local cerebral glucose metabolic rate in man. J Cereb Blood Flow Metab J NeurolNeurosurgPsychiatry1991;54:898—904. 198 1;1:37—51. 34. Eberling JL, Richardson BC, Reed BR, et al. Cortical glucose metabolism in 15. Lammertsma AA, Brooks DJ, Frackowiak R5, et al. Measurement of glucose Parkinson's disease without dementia. Neurobiol Aging l994;15:329—335. utilization with [‘8F]2-fluoro-2-deoxy-D-glucose: a comparison of different analytical 35. Pickel VM, Beckley SC, John TH, et al. Ultrastructural immunocytochemical methods J Cereb Blood Flow Metab 1987;7: 161—172. localization of tyrosine hydroxylase in the neostriatum. Brain Res l981;225:373—385. 16. Hutchins GD, Holden JE, Koeppe RA, et al. Alternative approach to single-scan 36. Jacobs BW, Butcher LL. Pathology of the basal forebrain in Alzheimer's disease and estimation of cerebral glucose metabolic rate using glucose analogs, with particular other dementias. In: Scheibel AB, Wechsler AF, eds. The biological substrates of application to ischemia. J Cereb Blood Flow Metab 1984;4:35—40. [email protected]:AcademicPress;1986:87—100. 17. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 37. Perry RH, Peny EK, Smith CJ, et al. Cortical neuropathological and neurochemical 1966; 17:427—442. substrates of Alzheimer's and Parkinson's diseases. J Neural Transm Suppi 1987;24: 18. Folstein MF, Folstein SE, Mc Hugh PR. Mini-Mental State: a practical method for grading 131—136. the cognitive state of patients for the clinician. J Psychiatr Ret 1975;12:189—198. 38. Huang S-C, Phelps ME, Hoffman EJ, et al. Noninvasive determination of local 19. Berg L. Clinical dementia rating. Psychopharmacol Bull 1988;24:637—639. cerebral metabolic rate of glucose in man. Am J Physiol l980;238:E69—E82. 20. Toorongian SA, Mulholland GK, Jewett DM, et al. Routine production of 2-deoxy 39. Brownell GL, Kearfott KJ, Kairento AL, et al. Quantitation of regional cerebral 2-['8Fjfluoro-D-glucose by direct nucleophilic exchange on a quaternary 4-aminopy glucose metabolism. J Cereb Blood Flow Metab 1983;7:919—924. ridinium resin. IntfRadAppllnstrum B l990;l7:273—279. 40. Evans AC, Diksic M, Yamamoto YL, et al. Effect of vascular activity in the 21 . Kearfott 10, Carroll LR. Evaluation of the performance characteristics ofthe PC 4600 determination of rate constants for the uptake of ‘0F-labeled-2-fluoro-2-deoxy-D- positron emission tomograph. J Comp Assist Tomogr 1984;8:502—513. glucose: error analysis and normal values in older subjects. J Cereb Blood Flow Metab 22. Koeppe RA, HolthoffVA, Frey KA, et al. Compartmental analysis of[' C]flumazenil 1986;6:724—738. kinetics for the estimation of ligand transport rate and receptor distribution using 41. Goto I, Taniwaki T, Hosokawa 5, et al. PET studies in dementia. J Neurol Sci positron emission tomography. J Cereb Blood Flow Metab l99l;l 1:735—744. 1993;l14:1—6. 23. Talairach J, Toumoux P. Co-planar stereotaxic atlas ofthe human brain. Thieme, New 42. Kalaria RN, Hank SI. Reduced glucose transporter at the blood-brain barrier and in York 1988. cerebral cortex in Alzheimer's disease. J Neurochem 1989;53:1083—1088. 24. Bevington PR. Data reduction and error analysis for the physical sciences. New York: 43. Marcus DL, de Leon MJ, Goldman J, et al. Altered glucose metabolism in microves Mc Graw-Hill; 1969:232—241. sets from patients with Alzheimer's disease. Ann Neurol l989;26:9l—94. 25. Marquardt DW. An algorithm for least-squares estimation of nonlinear parameters. J 44. Huang 5-C, Phelps ME, Hoffman EJ, Kuhl DE. Error sensitivity of fluorodeoxyglu SocApplMath 1963;ll:43l—44l. cose method for measurement of cerebral metabolic rate of glucose. J Cereb Blood 26. Sokoloff L, Reivich M, Kennedy C, et al. The [‘4C]deoxyglucosemethod for the Flow Metab l981;l:39I—40l. PET Measurements of Neuroreceptor Occupancy by Typical and Atypical Neuroleptics Peter F. Goyer, Marc S. Berridge, Evan D. Morris, William E. Semple, Beth A. Compton-Toth, S. Charles Schulz, Dean F. Wong, Floro Miraldi and Herbert Y. Meltzer Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; Departments ofRadiology and Psychiatry, Case Western Reserve University Medical School and University Hospitals, Cleveland, Ohio; and Department of Radiology, Johns Hopkins University Medical School, Baltimore, Maryland subjects who were b@ngtreated with ckzapine, an atypk@alanlipsy The goal of this study was to use PET and 11C-N-methylspiperone chotic drug. ResuI@ Among the three groups, there were significant (11C-NMSP)to measurethe differencesin relativeoccupancyof differences in5-HT@ indices, D2 indk@esand the ratio of 5-HT@to D2 serotonin (5-hydroxytryptamine-2 or 5-HT@) and dopamine-2 (D2) indices. With no overlap, the 5-HT@,index separated allsubjects who neuroreceptors in subjects being treated with typical or atypical recsived clozapne and the D2 index separated the remaining two antipsychotic drugs. Methods: We used PET and single-dose groups. Conclusion: Typkal antipsychotk@and atypical antipsychotic 11C-NMSP to measure receptor indices and relative receptor occu subjects do have differingpatterns of 5-HT@ and D2 relative receptor pancy of 5-HT2Areceptors in frontal cortex and D2 receptors in occupancy when measured with a single PE@scan, single 11C-NMSP basal ganglia infive subjects who were neuroleptic free, fivesubjects who were being treated with typical antipsychotic drugs and five radiotracer dose and no separately injected “cold―pharmaceutical. Key Words PET; carbon-i 1-N-methylspiperone; neuroreceptor cc cupancy ReceivedMar.24, 1995;revisionaccepted Nov.1, 1995. Forcorrespondenceorreprintscontact:PeterF.Goyer,MD,chiefofstaff,cleveland J NucIMed1996;37:1122—1127 vAMc(B).10,000BreCkSVIlieRd.,Brecksville,OH44141. 1122 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 7 •July 1996 InvitroN-methylspiperone(NMSP)hasbeencharacterizedas 5-HT2Areceptorsandlow occupancyof D2receptors,whilethe a high affinity dopamine-2 (D2) receptor ligand in rat and reverse is true of typical antipsychotic drugs. Meltzer (18,19) human caudate (1 ) as well as a serotonin-2 (5-hydroxytrypta suggested that the superior efficacy and low extrapyramidal mine-2 or 5-HT2A) receptor ligand in rat and human frontal side effects of clozapine may be related not to absolute receptor cortex (1 ). NMSP has been characterized in vivo as a D2 and occupancy ofthe individual 5-HT2A and D2 receptors but to the 5-HT2Aligand in mice (2), baboons(3,4) andhumans(5,6). [In extent of 5-HT2A receptor occupancy relative to D2 receptor accordance with the Serotonin Receptor Nomenclature Com occupancy. mittee (7), 5-HT2A will be the notation used for receptors This study was designed to use ‘‘C-NMSP as a single previously denoted as 5-HT2.] radiotracer to examine relative receptor occupancy produced by In 1983, Wagner et al. (5) reported the use of ‘1C-NMSP clozapine and by typical antipsychotic drugs of 5-HT2A recep with PET to image D2 receptors in human basal ganglia. tors in frontal cortex and of D2 receptors in basal ganglia to test Subsequently, Wong et al.
Load more

Recommended publications
  • Steven, Stacy (2012) the Pharmacology of the 5-HT2A Receptor and the Difficulty Surrounding Single Taret Models
    Steven, Stacy (2012) The pharmacology of the 5-HT2A receptor and the difficulty surrounding single taret models. MSc(R) thesis. http://theses.gla.ac.uk/3636/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] The pharmacology of the 5-HT2A receptor and the difficulty surrounding functional studies with single target models A thesis presented for the degree of Master of Science by research Stacy Steven April 2012 Treatment of many disorders can be frequently problematic due to the relatively non selective nature of many drugs available on the market. Symptoms can be complex and expansive, often leading to symptoms representing other disorders in addition to the primary reason for treatment. In particular mental health disorders fall prey to this situation. Targeting treatment can be difficult due to the implication of receptors in more than one disorder, and more than one receptor in a single disorder. In the instance of GPCRs, receptors such as the serotonin receptors (and in particular the 5-HT2A for the interest of this research) belong to a large family of receptors, the GPCR Class A super family.
    [Show full text]
  • Selective Labeling of Serotonin Receptors Byd-[3H]Lysergic Acid
    Proc. Nati. Acad. Sci. USA Vol. 75, No. 12, pp. 5783-5787, December 1978 Biochemistry Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate (ergots/hallucinogens/tryptamines/norepinephrine/dopamine) PATRICIA M. WHITAKER AND PHILIP SEEMAN* Department of Pharmacology, University of Toronto, Toronto, Canada M5S 1A8 Communicated by Philip Siekevltz, August 18,1978 ABSTRACT Since it was known that d-lysergic acid di- The objective in this present study was to improve the se- ethylamide (LSD) affected catecholaminergic as well as sero- lectivity of [3H]LSD for serotonin receptors, concomitantly toninergic neurons, the objective in this study was to enhance using other drugs to block a-adrenergic and dopamine receptors the selectivity of [3HJISD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of (cf. refs. 36-38). We then compared the potencies of various a combination of 50 nM each of phentolamine (adde to pre- drugs on this selective [3H]LSD binding and compared these clude the binding of [3HJLSD to a-adrenoceptors), apmo ie, data to those for the high-affinity binding of [3H]serotonin and spiperone (added to preclude the binding of [3H[LSD to (39). dopamine receptors), it was found by Scatchard analysis that the total number of 3H sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catechol- METHODS amine-blocking drugs. The IC50 values (concentrations to inhibit Preparation of Membranes. Calf brains were obtained fresh binding by 50%) for various drugs were tested on the binding of [3HLSD in the presence of 50 nM each of apomorphine (A), from the Canada Packers Hunisett plant (Toronto).
    [Show full text]
  • Antipsychotics (Part-4) FLUOROBUTYROPHENONES
    Antipsychotics (Part-4) FLUOROBUTYROPHENONES The fluorobutyrophenones belong to a much-studied class of compounds, with many compounds possessing high antipsychotic activity. They were obtained by structure variation of the analgesic drug meperidine by substitution of the N-methyl by butyrophenone moiety to produce the butyrophenone analogue which has similar activity as chlorpromazine. COOC2H5 N H3C Meperidine COOC2H5 N O Butyrophenone analog The structural requirements for antipsychotic activity in the group are well worked out. General features are expressed in the following structure. F AR Y O N • Optimal activity is seen when with an aromatic with p-fluoro substituent • When CO is attached with p-fluoroaryl gives optimal activity is seen, although other groups, C(H)OH and aryl, also give good activity. • When 3 carbons distance separates the CO from cyclic N gives optimal activity. • The aliphatic amino nitrogen is required, and highest activity is seen when it is incorporated into a cyclic form. • AR is an aromatic ring and is needed. It should be attached directly to the 4-position or occasionally separated from it by one intervening atom. • The Y group can vary and assist activity. An example is the hydroxyl group of haloperidol. The empirical SARs suggest that the 4-aryl piperidino moiety is superimposable on the 2-- phenylethylamino moiety of dopamine and, accordingly, could promote affinity for D2 receptors. The long N-alkyl substituent could help promote affinity and produce antagonistic activity. Some members of the class are extremely potent antipsychotic agents and D2 receptor antagonists. The EPS are extremely marked in some members of this class, which may, in part, be due to a potent DA block in the striatum and almost no compensatory striatal anticholinergic block.
    [Show full text]
  • Pharmacology Review(S)
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 200603 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology/Toxicology Review From: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IO NDA: 200603 Agency receipt date: 12/30/2009 Drug: Lurasidone hydrochloride Applicant: Sunovion Pharmaceuticals (Originally submitted by Dainippon Sumimoto Pharma America, Inc.) Indication: schizophrenia Reviewing Division: Division of Psychiatry Products Background: The pharm/tox reviewer and team leader concluded that the nonclinical data support approval of lurasidone for the indication listed above. Reproductive and Developmental Toxicity: Reproductive and developmental toxicity studies in rats and rabbits revealed no evidence of teratogenicity or embryofetal toxicity. The high doses in the rat and rabbit embryofetal toxicity studies were 3 and 12 times, respectively, the maximum recommended human dose (80 mg) based on a body surface area comparison. Carcinogenicity: Lurasidone was tested in 2 year rat and mouse carcinogenicity studies. These studies were reviewed by the division and the executive carcinogenicity assessment committee. The committee concluded that the studies were adequate and that there was a drug-related increase in mammary carcinomas in female rats at doses of 12 mg/kg and higher and a drug-related increase in mammary carcinomas and adenoacanthomas and pituitary pars distalis adenomas in female mice. The applicant also provided data from various studies showing that lurasidone significantly increases prolactin in several different species including rats and mice. Conclusions: I agree with the division pharm/tox conclusion that this application can be approved from a pharm/tox perspective. The division recommends that lurasidone be labeled with pregnancy category B.
    [Show full text]
  • Haloperidol Metabolites Elisa Kit Instructions Product #102119 & 102116 Forensic Use Only
    Neogen Corporation 944 Nandino Blvd., Lexington KY 40511 USA 800/477-8201 USA/Canada | 859/254-1221 Fax: 859/255-5532 | E-mail: [email protected] | Web: www.neogen.com/Toxicology HALOPERIDOL METABOLITES ELISA KIT INSTRUCTIONS PRODUCT #102119 & 102116 FORENSIC USE ONLY INTENDED USE: For the determination of trace quantities of Haloperidol Metabolites in human urine, blood, oral fluid. DESCRIPTION Neogen Corporation’s Haloperidol Metabolites ELISA (Enzyme-Linked ImmunoSorbent Assay) test kit is a qualitative one- step kit designed for use as a screening device for the detection of drugs and/or their metabolites. The kit was designed for screening purposes and is intended for forensic use only. It is recommended that all suspect samples be confirmed by a quantitative method such as gas chromatography/mass spectrometry (GC/MS). ASSAY PRINCIPLES Neogen Corporation’s test kit operates on the basis of competition between the drug or its metabolite in the sample and the drug-enzyme conjugate for a limited number of antibody binding sites. First, the sample or control is added to the microplate. Next, the diluted drug-enzyme conjugate is added and the mixture is incubated at room temperature. During this incubation, the drug in the sample or the drug-enzyme conjugate binds to antibody immobilized in the microplate wells. After incubation, the plate is washed 3 times to remove any unbound sample or drug-enzyme conjugate. The presence of bound drug-enzyme conjugate is recognized by the addition of K-Blue® Substrate (TMB). After a 30 minute substrate incubation, the reaction is halted with the addition of Red Stop Solution.
    [Show full text]
  • The Effect of Chronically Administered Lsd on the Serotonergic Nervous System of the Rat
    University of Rhode Island DigitalCommons@URI Open Access Master's Theses 1983 THE EFFECT OF CHRONICALLY ADMINISTERED LSD ON THE SEROTONERGIC NERVOUS SYSTEM OF THE RAT Bruce E. Fishman University of Rhode Island Follow this and additional works at: https://digitalcommons.uri.edu/theses Recommended Citation Fishman, Bruce E., "THE EFFECT OF CHRONICALLY ADMINISTERED LSD ON THE SEROTONERGIC NERVOUS SYSTEM OF THE RAT" (1983). Open Access Master's Theses. Paper 192. https://digitalcommons.uri.edu/theses/192 This Thesis is brought to you for free and open access by DigitalCommons@URI. It has been accepted for inclusion in Open Access Master's Theses by an authorized administrator of DigitalCommons@URI. For more information, please contact [email protected]. THE EFFECT OF CHRONICALLY ADMINISTERED LSD ON THE SEROTONERGIC NERVOUS SYSTEM OF THE RAT by Bruce E. Fishman A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Pharmacology and Toxicology UNIVERSITY OF RHODE ISLAND 1~3 ' .. MASTER OF SCIENCE DISSERTATION OF BRUCE E. FISHMAN Approved: Dissertation Committee Major Professor /~ Pmte+~ t!.i'. ~ UNIVERSITY OF RHODE ISLAND 1983 ABSTRACT Legitimate and illegitimate use of lysergic acid diethylanide (LSD) increased dramatically in the 1960 1 s. Since then, a number of studies have shown that LSD induces -psychotic symptoms in the user, suggesting a possible correlation between exposure to LSD and certain psychoses. This hypothesis is supported by repeated observations that LSD inhibits 5-HT systems in the brain and that central 5-HT systems may be implicated in certain psychoses. The present study was designed to test the hypoth­ esis that chronic administration of LSD to rats has an observable effect on 5-HT neuronal functioning in the brain.
    [Show full text]
  • Dopamine, More D2 Receptors Philip Seeman* and Shitij Kapur†
    Commentary Schizophrenia: More dopamine, more D2 receptors Philip Seeman* and Shitij Kapur† Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, ON Canada M5S 1A8 chizophrenia is a major therapeutic on both pre- and postsynaptic aspects by significance for previously medicated pa- Schallenge of modern medicine, and using an indirect method to measure the tients, but exhibited only a trend for pa- one of the last frontiers of brain research. levels of endogenous dopamine in patients tients who had never been medicated with The illness is defined by delusions, hallu- and controls. antipsychotic drugs. Despite this lack of cinations, disorganized behavior, and cog- Although numerous postmortem stud- statistical significance in this latter group nitive difficulties such as memory loss. It ies have consistently revealed D2 recep- of patients, the empirical findings of Abi- occurs in Ϸ1% of the world population tors to be elevated in the striata of patients Dargham et al. indicate that an increase in and usually first appears in early adult- with schizophrenia (9), the majority of the dopamine D2 receptors must occur, be- hood. Although antipsychotic medications postmortem tissues examined have come cause it is not possible for patients to show have dramatically improved the lives of from patients who have been treated with a greater increase yet not have a higher patients with schizophrenia, the causes of antipsychotics, raising the probability that number of D2 receptors. Thus, the paper the illness remain unknown. the drugs themselves contributed to the by Abi-Dargham et al. provides support Of the many contemporary theories of elevation of D2 receptors.
    [Show full text]
  • A Complete Assessment of Dopamine Receptor- Ligand Interactions Through Computational Methods
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 6 February 2019 doi:10.20944/preprints201902.0064.v1 Peer-reviewed version available at Molecules 2019, 24, 1196; doi:10.3390/molecules24071196 Article A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods Beatriz Bueschbell 1, Carlos A. V. Barreto 2, António J. Preto 2, Anke C. Schiedel 1 and Irina S. Moreira 2,3,* 1 PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, D-53121 Bonn, Germany; [email protected]; [email protected] 2 Center for Neuroscience and Cell Biology, UC- Biotech Parque Tecnológico de Cantanhede, Núcleo 04, Lote B, 3060- 197 Cantanhede, Portugal; [email protected]; [email protected]; [email protected] 3 Institute for Interdisciplinary Research, University of Coimbra *Correspondence: [email protected]; Tel.: +351 231 249 730 Abstract Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2- like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions > 2.5 Å and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions.
    [Show full text]
  • Impact of Depressogenic- and Antidepressant-Like
    Impact of depressogenic- and antidepressant-like challenges on monoamine system activities: in vivo electrophysiological characterization studies Chris A. Oosterhof Department of Cellular & Molecular Medicine University of Ottawa Thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy Degree in Neuroscience © Chris A. Oosterhof, Ottawa, Canada, 2016 Table of contents Table of contents ............................................................................................................. ii Acknowledgements ........................................................................................................ iv Statement of contributions .............................................................................................. v List of figures ................................................................................................................. vi List of tables .................................................................................................................. vii Glossary ........................................................................................................................ viii Abstract .......................................................................................................................... xi 1) Major depressive disorder ............................................................................................... 1 2) Monoamine systems.......................................................................................................
    [Show full text]
  • Adasuve, INN-Loxapine
    13 December 2012 EMA/91055/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Adasuve International non-proprietary name: loxapine Procedure No. EMEA/H/C/002400 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 7523 7455 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. Contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier .................................................................................... 8 Information on Paediatric requirements ....................................................................... 8 Information relating to orphan market exclusivity .......................................................... 8 Scientific Advice ....................................................................................................... 8 Licensing status ....................................................................................................... 8 1.2. Steps taken for the assessment of the product ....................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction ...................................................................................................
    [Show full text]
  • University of Groningen the Medicinal Chemistry of Arylpiperazines With
    University of Groningen The medicinal chemistry of arylpiperazines with potential antidepressant efficacy Mensonides, Marguerite IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2001 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Mensonides, M. (2001). The medicinal chemistry of arylpiperazines with potential antidepressant efficacy. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 28-09-2021 RIJKSUNIVERSITEIT GRONINGEN The Medicinal Chemistry of Arylpiperazines with Potential Antidepressant Efficacy PROEFSCHRIFT ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, Dr.
    [Show full text]
  • Receptor Binding Profile of Quinupramine, a New Tricyclic Antidepressant
    Receptor Binding Profile of Quinupramine, a New Tricyclic Antidepressant Hirohiko SAKAMOTO*, **, Nobuharu YOKOYAMA*, **, Shigekatsu KOHNO* and Katsuya OHATA* *Department of Pharmacology , Kyoto Pharmaceutical University, Yamashina, Kyoto 607, Japan **Biochemical Division , Research Laboratories, Nippon Shoji Kaisha, Ltd., Ibaraki, Osaka 567, Japan Accepted August 17, 1984 Abstract-The receptor binding profile, composed of the K;-values measured in eight different receptor binding models using rat brain membranes, is reported for the new tricyclic antidepressant quinupramine, 10,11 -dihydro-5-(3-quinuclidinyl) 5H-dibenz[b, f]azepine, and three reference compounds with a tertiaryamine side chain. Quinupramine was found to possess high affinity for muscarinic cholinergic and histamine Ht receptor binding sites in rat brain, whereas its affinity for imipramine binding sites was only one seventieth that of imipramine. Receptor binding profiles of the reference compounds were almost similar to that of quinupramine , except in the case of imipramine binding sites. Tricyclic antidepressants are known to be clidinyl [phenyl-4-3H]benzilate (42 Ci/ inhibitors of norepinephrine and serotonin mmol), [pyridinyl-5-3H]pyrilamine (28 Ci/ reuptake into nerve terminals. This action was mmol) and [phenyl-4-3H]spiperone (17 Ci/ also believed to be responsible for their mmol) were purchased from Amersham , therapeutic effects and probably involved Buckinghamshire, England. [N-methyl-3H] presynaptic sites (1). In addition, recent imipramine hydrochloride (75 Ci/mmol) was reports suggest a direct interaction of tricyclic from New England Nuclear, Boston, MA , antidepressants with a variety of seemingly U.S.A. 3H-Ligands were stored at -20°C postsynaptic sites. These evidences have and diluted in standard assay buffer before been obtained through the interaction of use.
    [Show full text]