Monoamine Oxidase and their Inhibitors

286 Pages·2011·3.623 MB·English

by  Moussa B.H. Youdim and Peter Douce (Eds.)

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
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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