Monoamine Oxidase and their Inhibitors PDF
Preview Monoamine Oxidase and their Inhibitors
International R E V I E W O F Neurobiology Volume 100 SERIES EDITORS R. ADRON HARRIS Waggoner Center for Alcohol and Drug Addiction Research The University of Texas at Austin Austin, Texas, USA PETER JENNER Division of Pharmacology and Therapeutics GKT School of Biomedical Sciences King’s College, London, UK EDITORIAL BOARD ERICAAMODT HUDAAKIL PHILIPPEASCHER MATTHEWJ.DURING DONARDS.DWYER DAVIDFINK MARTINGIURFA BARRYHALLIWELL PAULGREENGARD JONKAAS NOBUHATTORI LEAHKRUBITZER DARCYKELLEY KEVINMCNAUGHT BEAULOTTO JOSE´ A.OBESO MICAELAMORELLI CATHAYJ.PRICE JUDITHPRATT SOLOMONH.SNYDER EVANSNYDER STEPHENG.WAXMAN JOHNWADDINGTON AcademicPressisanimprintofElsevier 32JamestownRoad,LondonNW17BY,UK Radarweg29,POBox211,1000AEAmsterdam,TheNetherlands LinacreHouse,JordanHill,OxfordOX28DP,UK 225WymanStreet,Waltham,MA02451,USA 525BStreet,Suite1900,SanDiego,CA92101-4495,USA Firstedition2011 Copyright(cid:1)2011,ElsevierInc.AllRightsReserved Nopartofthispublicationmaybereproduced,storedinaretrievalsystem ortransmittedinanyformorbyanymeanselectronic,mechanical,photocopying, recordingorotherwisewithoutthepriorwrittenpermissionofthepublisher PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRights DepartmentinOxford,UK:phone(þ44)(0)1865843830;fax(þ44)(0)1865853333; email:permissions@elsevier.com.Alternativelyyoucansubmityourrequestonline byvisitingtheElsevierwebsiteathttp://elsevier.com/locate/permissions,andselecting ObtainingpermissiontouseElseviermaterial Notice Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersons orpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuse oroperationofanymethods,products,instructionsorideascontainedinthematerial herein.Becauseofrapidadvancesinthemedicalsciences,inparticular,independent verificationofdiagnosesanddrugdosagesshouldbemade ISBN:978-0-12-386467-3 ISSN:0074-7742 ForinformationonallAcademicPresspublications visitourwebsiteatelsevierdirect.com PrintedandboundinUSA 11 12 13 14 10 9 8 7 6 5 4 3 2 1 CONTRIBUTORS Numbersinparenthesesindicatethepagesonwhichtheauthors’contributionsbegin. Yukihiro Akao (85), United Graduate School of Drug Discovery and Medical Information Sciences,GifuUniversity, Gifu,Japan TamarAmit(127,191),EveTopfCentreofExcellenceforNeurodegenerative Diseases and Department of Molecular Pharmacology, Technion-Rappaport FacultyofMedicine, EfronStreet, P.O. Box9697, Haifa, Israel Orit Bar-Am (191), Eve Topf Centre of Excellence for Neurodegenerative Diseases and Department of Molecular Pharmacology, Technion-Rappaport FacultyofMedicine, EfronStreet, P.O. Box9697, Haifa, Israel Claudia Binda (1), Department of Genetics and Microbiology, University of Pavia, Pavia, Italy Marco Bortolato (13), Department of Pharmacology and Pharmaceutical Sciences,SchoolofPharmacy,UniversityofSouthernCalifornia,LosAngeles, California,USA L.M.Chahine(151),PennComprehensiveNeuroscienceCenter,Universityof Pennsylvania, Philadelphia, Pennsylvania,USA Gavin P. Davey (43), Department of Biochemistry, Trinity College, Dublin, Ireland Dale E. Edmondson (1), Department of Biochemistry, Emory University, Atlanta, Georgia,USA JohnP.M.Finberg(169),DepartmentofMolecularPharmacology,Rappaport FacultyofMedicine, Technion,Haifa, Israel Werner J. Geldenhuys (107), Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA Ken Gillman (169),Psychotropical Research,Bucasia, Queensland, Australia KeikoInaba-Hasegawa(85),DepartmentofNeurosciences,GifuInternation- alInstituteof Biotechnology, Kakamigahara, Gifu, Japan Ka´lma´n Magyar (65), Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary; Neurochemical Research Unit, Hungarian AcademyofSciences,Budapest, Hungary ix x CONTRIBUTORS SilviaA.Mandel(127),EveTopfCentreofExcellenceforNeurodegenerative Diseases and Department of Molecular Pharmacology, Technion-Rappaport FacultyofMedicine, EfronStreet, P.O. Box9697, Haifa, Israel Wakako Maruyama (85), Department of Cognitive Brain Science, National ResearchCenterfor Geriatrics and Gerontology,Obu,Aichi,Japan Andrea Mattevi (1), Department of Genetics and Microbiology, University of Pavia, Pavia, Italy Andrew G. McDonald (43), Department of Biochemistry, Trinity College, Dublin, Ireland Makoto Naoi (85), Department of Neurosciences, Gifu International Institute ofBiotechnology,Kakamigahara,Gifu,Japan PeterRiederer(127),ClinicalNeurochemistry,NationalParkinsonFoundation Centre of Excellence Laboratories, Clinic and Polyclinic for Psychiatry, Psychosomatic, and Psychotherapy, Medical School, University of Wu¨rzburg, Wu¨rzburg,Germany ElisendaSanz(217),InstitutdeNeurocie`nciesandDepartamentdeBioqu´ımi- ca i Biologia Molecular, Universitat Auto`noma de Barcelona, Cerdanyola del Valle`s(Barcelona), Spain JeanC.Shih(13),DepartmentofPharmacologyandPharmaceuticalSciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA; Department of Cell and Neurobiology, Keck School of Medicine;Universityof SouthernCalifornia, Los Angeles,California,USA M.B. Stern (151), Penn Comprehensive Neuroscience Center, University of Pennsylvania, Philadelphia, Pennsylvania,USA Keith F. Tipton (43), Department of Biochemistry, Trinity College, Dublin, Ireland Mercedes Unzeta (217), Institut de Neurocie`ncies and Departament de Bio- qu´ımicaiBiologiaMolecular,UniversitatAuto`nomadeBarcelona,Cerdanyo- ladel Valle`s(Barcelona), Spain Cornelis J. Van der Schyf (107), Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA OrlyWeinreb(127,191),EveTopfCentreofExcellenceforNeurodegenerative Diseases and Department of Molecular Pharmacology, Technion-Rappaport FacultyofMedicine, EfronStreet, P.O. Box9697, Haifa, Israel MoussaB.H.Youdim(127,191),EveTopfCentreofExcellenceforNeurode- generative Diseases and Department of Molecular Pharmacology, Technion- Rappaport Faculty of Medicine, Efron Street, P.O. Box 9697, Haifa, Israel; Departmentof Biology, Yonsei University, Seoul, South Korea PREFACE Thisvolumewillbeconcernedwithanimportantenzymethatwasidentified intheliverofrabbitssome90yearsago,whichmetabolizedtyraminebyoxidative deamination. In 1934 Blaschko demonstrated that this enzyme metabolized primary,secondary,andtertiaryamines,includingadrenalineandnoradrenaline, and that tyramine oxidase and noradrenaline oxidase were the same enzyme. Zeller gave it its name as monoamine oxidase (MAO) to differentiate it from diamineoxidases.Itsrelevancetopsychiatrywasrecognizedbyserendipityinthe early1950s,whereiproniazid,adrugfortreatmentoftuberculosis,wasdiscovered to be its inhibitor and introduced into the clinic as the first antidepressant. The contributions ofstudiesonMAOand its inhibitor to pharmacologyand physio- logical actions of biogenic amine neurotransmitters can not be exaggerated. Numerous MAO inhibitors were developed by the pharmaceutical companies as antidepressants. Subsequent reports of side effects of MAO inhibitor antide- pressants, known as the "cheese reaction," resulting in hypertensive crisis led almost to this appearence of these drugs from the clinic. Between 1965 and 1968, evidences were provided that MAO exists in at least two forms. Johnson named these as MAO-A and MAO-B, where the irreversible propargylamine- derivedinhibitor,clorgyline,wasshowntobeaselectiveinhibitorofMAO-A.The neurotransmitters serotonin, noradrenaline, and adrenaline were identified as substrates of MAO-A, while phenylethylamine and benzylamine are substrates of MAO-B. Dopamine and tyramine were considered substrates for both enzymes. Knoll and Magyar reported that another propargylamine-derived in- hibitor, L-deprenyl (later named selegiline), was a selective inhibitor of MAO-B. Theimpactofthesefindingswastoresultinaflurryofstudieswiththeseselective inhibitors to determine the distribution, function, and physiological and neuro- pharmacological roles of the two enzymes invarious animal and human tissues and more profoundly in the brain. One important intriguing pharmacological aspectofL-deprenylwasthatatitsselectiveMAO-B-inhibitorydosage,itdidnot induce the"cheesereaction"inanimalstudies,thusbeingthefirstMAOinhibi- tory devoid of such property. This feature and predominance of MAO-B in human brain extrapyramidal regions was the impetus for Birkmayer, Riederer, and Youdim to initiate a clinical trial with L-deprenyl in Parkinson’s disease in xi xii PREFACE 1974–1975,withpositiveresultsandconfirmedbyothergroups.In1983thesame group suggested that L-deprenyl in Parkinson’s disease may induce longevity in parkinsonian patients and was attributed to prevention of the degeneration of nigrostriataldopamineneurons(neuroprotection).Thisfindingwassupportedby identificationofthedopaminergicneurotoxin,MPTP(N-methyl-1,2,3,6-tetrahy- dropyridine), that caused parkinsonism in drug designer addicts. MPTP, a sub- strateofMAO-B,isaninertsubstance;however,wheninjectedintoanimals,itis þ converted to the neurotoxin, MPP by MAO-B, which then is taken up by nigrostriataldopamineneuronsandcausesneurodegenerationofdopamineneu- rons in mice, cat, dogs, and human and nonhuman primates. Heikkila and colleagues in 1984 published the exciting paper which showed that when mice werepreinjectedwithL-deprenyl,butnotwithclorgyline,itpreventedtheMPTP- induceddegenerationofthedopamineneurons.Thus,theconceptofneuropro- tection was born, whichinitiated numerous neuroprotectivestudies with MPTP asthemodelofParkinson’sdisease.ThedemonstrationofMAO-Aand-Bbeing differentproteins,theanti-ParkinsonactivityofL-deprenylanditsneuroprotective activity, as confirmed by several groups, led to the search and development of numerousirreversibleandreversibleselectiveandspecificinhibitorsofMAO-A, as antidepressants, and MAO-B as anti-Parkinson drugs, devoid of the cheese reaction. Much credit should go to Moshe Da Prada for advancing the MAO inhibitors, who developed successfully the antidepressant reversible MAO-A inhibitor, moclobemide, and the first reversible MAO-B inhibitor, lazabemide, neitherofwhichinitiatedthecheesereaction. L-DeprenyldidnotreachtheUnitedStatesuntil1989,some15yearsafterour firstdescriptionofitsanti-Parkinsonaction.Thereisamisconceptionthatnodrug isadruguntilitisapprovedbyFDAintheUnitedStates.Nevertheless,L-deprenyl waspatentedasanorphandrugintheUnitedStatesandgiventhenameselegi- line.Between1975and1982,therewasabeliefthattherewassomethingunique about the pharmacological action of L-deprenyl (selegiline) that differentiated it from other MAO inhibitors. But during this period, Youdim and colleagues identified the second propargylamine-derived MAO-B inhibitor, AGN1135, whichwashighlysignificantlymoreactivethanL-deprenyl.Thisdrugeventually became the second MAO-B inhibitor anti-Parkinson drug named, rasagiline. Rasagilineisdifferentiatedfromselegilinebytheobservationsinwhichboththe parentcompoundanditsaminoindanmetaboliteareneuroprotectiveandMAO- B inhibition is not a prerequisite for neuroprotection. Indeed a recent clinical study,ADAGIO,inparkinsoniansubjectswithrasagilinehasindicateditmaybe the first disease-modifying neuroprotective drug. Much has been learned about the molecular mechanism of the neuroprotective activities of selegiline and rasagiline, which we hope can contribute to the development of even better antidepressantsandanti-Parkinsondrugs. PREFACE xiii Thisvolumeisacollectionofchaptersbymanyoftheleadingindividualsthat have helped to shape and advance the research in MAO and its more recent developments. The volume starts with the fascinating chapter by Binda, Mattevi, and Edmondson which describe the fundamental differences between MAO-A and MAO-B with regard to their protein structures as shown by X-raycrystal struc- tureanalyses.IdenticalintheirFAD-bindingsites,theydifferinthestructuresof theiractivesitesoppositetheflavincofactor.Thecavitystructuresdifferconsider- ablyforsubstrateentrance.Bothenzymesaredimericintheirmembrane-bound forms. These findings are essential for the development of new compounds as MAO-inhibitors. They describe the mechanism and structural requirement for bindingoftheselectiveMAOinhibitors. Both isoenzymes are mitochondrial-bound proteins, catalyzing the oxidative deaminationofbiogenicamines/neurotransmitters.AsBortolatoandShihelab- orate here MAO-A and MAO-B derive from a common ancestral progenitor gene,arelocatedattheX-chromosome,andshare70%structuralidentity.They canbedistinguishedbytheirsubstrateandinhibitorspecificityandselectivity.As such,itisnotfarfetchedtoassumethatanydysregulationsmayleadtoavarietyof behavioral/social alterations with particular phenotypes including anxiety, de- pression, attention-deficit-hyperactivity disorder, impulse-control disorders, au- tism,psychosis,etc. It is another highlight of this book that the Doyen of MAO/MAO-inhibitor biochemistry,Tiptonetal.deliveredanextensiveessayonthekineticpropertiesof bothenzymesandtheirinhibition.Perhaps,itisthelastofsuchchaptersdealing with ‘‘classic biochemistry’’ for the next decade (and until biochemistry again becomesimportantinmolecularbiologywhenitisfundamentalagaintotranslate staticmeasuresinto‘‘functions’’). One of the reasons that MAO-inhibitors of the 50th and 60th of the past century could not be further used and developed has been the liver toxicity of many such compounds based on a hydrazine structure and the development ofhypertensivecrisescalledcheeseeffect(asitwasthoughtthatdietcomposedof cheese,beer,andredwineinpatientsonMAO-inhibitortherapywouldbecausal forsuchbloodpressurecrisisbecauseofthesympathomimeticaminespresentin such diets which are substrates of MAO and prevention of their metabolism in MAOtreatmentcanresultinthehypertensivecrisis). Finberg and Gillman in an extremely elegant and comprehensive review describe the hard facts about the potential of MAO-inhibitors to release the cheese effect. Importantly, they describe the translation of animal experimental work and the patient response when using such medication under clinical dose regime. They describe the mechanism why selective inhibitors of MAO-B in contrasttoMAO-Ainhibitorsdonotinducethecheesereaction. xiv PREFACE MagyardelineatesthedevelopmentofthefirstselectiveandspecificMAO-B inhibitor selegiline (L-deprenyl) whose studies initiated the revival of interests in MAO-Aand-Binhibitorsaspsychotropicdrugs.Here,heconcentratesonselegi- linemetaboliteselaboratingtheir potentialfor neuroprotection(desmethylselegi- line, selegiline-N-oxide) as well as their possible harmful action (amphetamine, metamphetamine). As one of the discoverers of selegiline, Magyar reviews the pharmacokineticpropertiesofselegilineinexperimentalstudiesandthuscritically viewssomeunknownpropertiesofthisirreversibleMAO-Binhibitorwithoutthe cheeseeffect. Molecularbiologicalandgeneticaspectsofselegiline’sactionarecoveredby Naoi etal. Inthis chapter, theynot only pointto differentiation of selegiline and rasagilinemolecular properties,butratherfocusonthesofaroverlookedimpor- tant aspects, namely, the role of MAO-A in neuronal death and protection mechanismsbyMAO-Binhibitors.Thisaspectisofmajorimportanceasunder- standing of the interaction uncovers new lines of strategies to fight neurodegeneration. SilviaMandel’sworkinggroupconcentratesonthemolecularpharmacology and molecular biology of rasagiline and selegiline and follow-up inhibitor com- pound. In addition, the role of the presumptive neuroprotective and neurores- torativemetaboliteofrasagilineaminoindanishighlightedandthataminoindan could contribute to the neuroprotective activityof the parent compound rasagi- line.EvidenceforParkinson’sdisease-modifyingactionofrasagilineispresented asbeingthefirstneuroprotectivedrugforthisdisorder. Thislineofargumentsforaprotectiveroleofrasagilineisfurtherenlargedby Chahine and Stern by focusing on clinical trials, their outcome, and future developments. Unzeta and Sanz presents new data on another propargylamine-derived MAO inhibitor, PF 9601 N, a compound with a high potency and selectivity to inhibitMAO-B.Invivoandinvitromodelsdemonstrateneuroprotectivepotential so that there is a new promising candidate for the treatment of Parkinson’s disease. Some 20 to 30 years ago, we were confronted with what was called ‘‘dirty drugs’’ meaning that the multiple pharmacological action of many medications not only improved the patient’s condition but rather and frequently led to unwanted side effects and adverse reactions. Although potent in their clinical beneficialeffectsspecific/monocausaldrugsweredevelopedwiththeimplemen- tation to create medication with both a significant beneficial effect and less side effects/adverse reactions. This concept, however, has to be reconsidered on the basisthatneurodegenerativedisordersatleastaremultitransmitterdisorders,they are mostly sporadic and therefore multigenetic, and they are very much depen- dent on multiple environmental influences. Therefore, Van der Schyf and Gel- denhuys focus the important chapter on ‘‘multimodal,’’ ‘‘multifunctional’’, PREFACE xv designedmultipleligands(DMLs)drugdevelopments.Delineatingargumentsand ways for this concept means that, by using modern knowledge about receptor subtypes, their preferred localization in (sub)regions of the human brain, etc., multiple pharmacological actions will indeed lead to more specific treatment of such devastating neurodegenerative disorders like Parkinson’s and Alzheimer’s diseasesandalower potential forsideeffects/adversereactions.Thusthe‘‘dirty drugs’’havelosttheir‘‘dirtypart,’’thatis,sideeffects/adversereactionsandhave converted to admire the positive part of ‘‘multifunctional drugs,’’ that is, the beneficialeffect. Weinreb and her cooperators have used this concept in developing new multitarget drugs for Parkinson’s disease, for example, M30, M30 S, and HLA- 20, and Alzheimer’s disease, for example, ladostigil. These drugs are the first brain-selectiveMAO-Aand-B-inhibitors,withlittleinhibitionofsystemicMAO, thatdonotgiveacheesereactionincontrasttotheolderdrugsuchasphenelzine andtranylcypromine.Thesedrugshavetrueantidepressant,anti-Parkinson,and anti-Alzheimer activity in animal model studies. The M30 series of compounds arebrainpermeableandhavetheuniquepropertythattheyhaveneurorestora- tive activity in vivo. They increase endogenous BDNF, GDNF, VEGF, HIF, and erythropoetin.Thereisnewhopethatthesedrugswillhelpourpatientsatleastto minimize their burden if it would not be possible to protect their neurons from degenerativeprocesses. Altogether,thisbookoffersuniqueaspectsandawiderangeofnovelresearch and developments into the field of MAO-A and MAO-B inhibitors in order to createnewandmorespecificmedicationformentalaswellasneurodegenerative disorders. STRUCTURAL PROPERTIES OF HUMAN MONOAMINE OXIDASES A AND B ClaudiaBinda1,AndreaMattevi1andDaleE.Edmondson2 1 DepartmentofGeneticsandMicrobiology,UniversityofPavia,Pavia,Italy 2 DepartmentofBiochemistry,EmoryUniversity,Atlanta,Georgia,USA Abstract I. Introduction II. CrystallizationofPurifiedMAO-BandMAO-A III. StructureofHumanMAO-B IV. StructureofHumanMAO-AandComparisonwithRatMAO-A V. InsightsintoMembraneBindingofMAO-AandMAO-B VI. StructuralBasisforInhibitor-BindingSpecificitiesofMAO-AandMAO-B VII. ConclusionsandFutureProspects Acknowledgments References Abstract ThestructuralelucidationsofhumanmonoamineoxidasesAandB(MAO-A and -B) have provided novel insights into their similarities and differences. Al- though the enzymes exhibit (cid:1)70% sequence identities, highly conserved chain folds, and are structurally identical in their flavin adenine dinucleotide (FAD)- bindingsites,theydifferconsiderablyinthestructuresoftheiractivesitesopposite the flavin cofactor. MAO-A has a monopartite cavityof (cid:1)550 A˚3, and MAO-B exhibits a bipartite cavity structure with an entrance cavity of 290 A˚3 and a substratecavityof(cid:1)400A˚3.Ile199functionsasaconformational‘‘gate’’separat- ing the two cavities. Both enzymes are anchored to the outer mitochondrial membraneviaC-terminalhelicaltails.Loopstructuresarefoundattheentrances to their active sites at the membrane surface. Although the crystal structure of humanMAO-AismonomericwhileMAO-Bisdimeric,bothenzymesaredimeric intheirmembrane-boundforms.Dimerizationmaybeimportantforthefavorable orientationoftheresultantproteindipolemomenttowardtheanionicmembrane surface. INTERNATIONALREVIEWOF 1 Copyright2011,ElsevierInc. NEUROBIOLOGY,VOL.100 Allrightsreserved. DOI:10.1016/B978-0-12-386467-3.00001-7 0074-7742/11$35.00
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