Note: Descriptions are shown in the official language in which they were submitted.
2a3:~33
NE~ U8E 0~ N~DA RBC~EP~!OII. AN''l'A~:ONIE~t!3
The invention ralates to the n~w use ~ ~ntagonists
of the N-m~thyl-~-a~par~at~ ~NMDA3 receptor a~mplex and
their~ physioloyically aompatible s~lts ~s pharmaceuti~l
a~ants ~or the preven~i~n ~r treatment vf ~hronia
neurode~enerative di~e~e~, a~ well ~ to pharmaceutical
a~en~, w~ich cont~in the~e aompound~
Hi~h aonaentrations o~ eXoitatory amino ~ld~ (EAA)
such a~ glutamate tGLU~ and a~par~a~ (ASP~ (Fonnum, F.,
J. Ne~rochem~ 42~ 84) are pre~ent in the aentral
nervou~ ~y~tem o~ m~m~als, including m~n. For ths
exci~tory amino acid~ there exist di~eren~ Xeaeptor3
which ar~ iden~ifle~ a~r-ordi~ thelr ~pecific agoni~s
as N-methyl-D-a~par-~ate ~MDA), ~aina~ t~A) and
~ui quila~e (~IS~ raceptor~
~ he NMDA recep~r i~ th~ b~t char~¢te~ized receptor
~or EAA in the ~rain and rep~e~ent~ a complex unit, who~e
normal $unation i~ d~pend~n~ o~ the dynamic balance
batween differ~nt po~enti~ting and inhi~i~ory ~a~tors.
~arious n~urologic~l ~yndrome~ are a~ated by its
~un~on.
Thus, anticonvul~iv~, anxl~lyti~ an~ mu~c~e-relaxing
e~f~ck~ oocurriny a~ in ~pilep~y, a~ well as anxi~ty
sta~e~, ~pas~icity, and p~o~eativ~ e~ects on nerve aell
damage as ~ re~ult o~ i~chemia~hypoxi~ ~8im4n, R.~. et
al~, Soience ~ 850-8~ 4), hypo~lyc~mia (W~elo~h,
T., 8aiencQ a30; 6~1-6B3, 1985~ and Qpil~p~y (~hai~ D.W.
et a~., Y. N~uro~ci ~s 1~5-196, l9B8) ha~e ~een dssaribed
~or ~MDA a~tagoni~k~.
'~t~3 ~33
Al~hough there are ~ef~renaes ~hat ~n ~hrorlla
neuro~egenerative di~ea~es, suoh aB tluntington'~ dt~ea~
~nd Alzheim~r'~ isease (Greenamyr~, J.T. ~ al., Prog.
Neurop ychopharmacol., ~iol. Psychiat. 12: 412-430,
1988),
amyotrophic lat~ral scl~rosi3 and olivopontocerebella~
degeneration (Pl~itaki~, A. et al., Ann. Neur~, ~Z: 575-
579, 1987; Science 216: 193-196, 1~82~ excita~ory amino
aci~s are important in pathophysioloyy, so ~ar it ha~ not
been found that ~pRCi~iC antagoni~t~ of EAA have ~
preventive action on the degener~tion of hrain cell~.
Aqainst thi~ background, th~ flnd1ny acco~ding to
th~ invention is surprising that NMDA antagonist~ prev~nt
the degeneration of dopaminer~ic neu~ons and th~s
represent e~ective pr~ven~iv~ pharmaceutical agent3 with
neuroproteative action.
Pa~kinsan ' s di~e~se al~o b~longs to the ~roup of
ahronia neurodegenerative disease6, which arQ triggersd
~y the pro~ressi~e des~otion e~pe~i~lly of dop~mlnergic
neurons in the substantia nigra o~ the brain~ The
al~niaal ~ymptoms o~ Parkin~on'~ di3ease are cau~ed by
neuro~oxins ~uoh as l-m~thyl q-phenyl-l, 2, 3, ~-
t~trahy~ropyridin~ (~PTP) or it~ n~urotoxic mettabolit~ 1-
m~thy~-4-ph~ny~-pyridinium ion (MP~) (Lanyston~ Y.W~ et
al., Soience ~12: 97~-980, 19fi3).
To prov~ ~h6 protectivs aotion o~ th~ oompounds
accordinq to the invention the ~oxic metabolite MPP~ was
in~eated loaally into the substantla nigra o~ rat~ and
thus caused a quickly pro~re~sing ~eg~n~ration of the
dop~lne n~uron~. Th~ ~imultaneou~ local administration
of ~ ctivu NMDA rec~ptor anta~oni~t 2-amino-7-
pho~phonoheptanoic a~id (AP-7) aanael~ the
neurodsgenerative eff~ct o~ MPP~ on the dopamine neuron~
almost aompletely (~able l).
;3
Preven~ive aation oE AP-7 in dl~rent do~e~ and at
dif~erent ~ime~ aft~r loaal ooadmini~trakion with MP~
(0.025 mio~mol per ~ide) in the ~u~t~nk~a nigra par~
aompacta ~SNC~ o~ rat~. AP-7 wa~ ln~e~t~d in ~i~fer~nt
dose~ together with ~PP~ ~h the right SNC of aach. The
left 5NC o~ ea~h wa~ tr~ated with MPP~ an~ served only as
a correspon~ing lesion ~ontrol~ At dif~erent time~ a~tQr
loaal in~e~tion the animal~ wer~ d~capitate~, thP braing
~ere ~emoved, ater in-~itP ~ixing~ and the number o-f
intact, typl~al dopamine neuron~ o~ the SNC was aounted
~nder a light microsGope with br~in ~e~ti~n~, ~tained
with cresyl viole~, of ~ defin~ plan~ o~ s~ction
(coronary e&ction direatly ro~tr~l to the ih-~ e~tion
~itR~. ~x:p less than 0.05 xx:p le~s tha~ 0.01; xxx:p
le~ than 0.001; t te~t V6. corre~ponding control~.
SNC Treatment Tim~ n Number o~ int~ct
neurons (~verage
+ SEM
left vehicle 4 h 8 158 ~ 7
rl~h~ v~hicl~ 161 + 6
l~ft MPP~ 4 h 3 18 ~ 4
ri~ht ~PP I AP-7 0.0~5 26 ~ 2
mi~romol
le~t MPP~ 4 h 4 27 t 7
ri~ht MPP~ ~ AP-7 0.1 91 + 24 x
micromol
le~t MP~ 4 h 9 30 + 4
right MPP~ + ~P-7 0.25 128 ~ lC XXx
micromol
le~t MPP~ a h 4 ~5 ~ 8
righ~ ~PP~ + AP-7 0.25 79 1 ~ XX
miaromol
left MPP 24 h 4 14 + 6
right MPP~ AP-7 0.25 ~6 + 16 X
micromol
~OQ~ 33
on the baei~ o~ sal~ research, a~l~agoni3t~ o~ th~
NMDA r~aeptor complex are ~uita~l~ Por prevantion o~
ahroni~ neurode~enerative disea~ee, ohar~cterized by
~lraumsaribed and well-de~ined n~uron los~, ~or example,
for ~he pr~v~ntion o~ degeneration of dopa~ne~gic
neurons ln Parkinson'~ di~ease, cholinergic neurons in
Alzheimer's disea~ or cortical and ~pinal motor neurons
in amyotrophic lateral sclerosis and olivopontocereb~llar
dagener~tion. This neuroprot~ctive action is ~pecific
~or an~agonists of the ~MDA reaeptor aompl~x. The activa
aqents should be admini~ered to p~tient3 with a ~amily
history o~ chronic neurodegeneratlve disease, with low
level symptom~ which may lead up to ~uch di~eas~, and/or
patient over a a~rtain a~e a~ whi~h ~uch di~ea~s
frequently occur.
The followin~ compounds or th~ir physio~ogic~l~y
compatible salts are ~uita~le ~or this new use:
(1) CompetitiYe NMDA antagoni~t~ ~u~h a~, for
example, 2-aminu-7-phosphonoheptanoia aaid (AP-7) and
analogs; 3-((~ aarbqxy-piperazin-4-yl)-propyl-1-
pho3phonic acid ~CPP~ and analog~, Cifi~4 ~pho~phonom~thyl-
2~p~p~ridine carboxylic acid ~CGS 197~5). 2-amino-7-
~hosphonoheptanoia aaid ~AP~7) iB a comp~titivs NMDA
antaguni~t and thus act~ direatly on the ~MDA binding
25 ait~ o~ the receptor aomplex.
(2) Non~omp~titiYe NMDA antagonist~ ~uah a~, for
example, (+)10,11-d$hydro-5-m~thyl-5H-dibenzo-~a,d]-
cyalohepten-5,10-imin~ (MR-~01), memantin~ and other
I
3 3
aman~adine analog~, ~etamin~ and analo~ nprodil and
analog6.
(~) Antagonl~t~ Q~ glyoin~ bindiny ~ite~ ~i.e.,
non-oo~petitive antagonists of the NMDA re~eptor ~omplex)
such as, ~r examplQ, ~ynurenic acid and ~nalo~
hydroxy-3-am~no-pyrrolldin-2-o~ 66) and analog3.
~ 4~ ~olyamin~s which are non~aompetltive
ant~goni~t~ ~u~h ~s, for ~xample, spermine and
~permidine.
(5) Anticholinerglcs with NMDA antayonl~k aotion
su~h as, for example, biperiden, trih~xiphenidyl.
(6) Inhibitors o~ the excitatory amino acid
synthes is .
Esp~cially suitabl~ according to th~ invention are
tho~e NMDA re~eptor~ antagoni~t~, which ~pecl~ically act
preventl~ely on the de~e~era~ion o~ dopaminer~i~ neurons
triggered by tha neurstoxin MPP~. The su~tan~e6 in (3)
and (4) are antagoni~t~, but int~rfare with other,
di~ferent bindin~ site~ on the rec~ptor c~mpl~x than the
~ubstan~ in ~1) a~d ~2). The subst~nces in ~3) and t4)
are NMDA antagonists, but tho~e o~ the non-~ompetitiva
type, ~in~e they aat on modulating binding ~ite6 of the
NMDA receptor complex, i.e., not on th~ NMDA binding ~ite
it~nl~.
~5 The invention also compri~ ph~rmaceutiaal agents,
whiah contain said aompound~, ~heir produa~ion a~ well as
the use o~ the compounds acaording to the invention ~or
the production o$ pharmaceu~ioal agents, which aro us~d
2 ~ 3 .3
for treatment and prophylaxi~ o~ th~ abova-n)entioned
di~ease~. ~he pha~maGQutia~l agent~ ~r~ prod~d
according to process~s lcnown in the art, by the active
in~redient, with suitahl-a ~ehir~s, ~uxl.lla~y ~gen~3
andJQr additlveg, ~eing put in the ~orm o~ a
pharmaceutical preparation, which i5 suitable especially
for en~eral or p~renteral admin~stratiosl. There are
suitable a~ auxiliary a~ent~ for the desir~d
pharmaceuticAl agent ~ormu~ ation the l~ert organ$c and
inorganic exclpients kn~wn to one ~illed in the art such
a~, e.~., water, ~elatin, gum arabic, la~to3e, ~tarch,
m~gnesium stearate, talc, vegatable oils, polyalkylene
glycols, etc. Optionally, they ~an fur~her ~nt~in
preservatives, ska~illzex~; wetting agents, emulsi~iers
or salt~ for changing th~ o~motla pres~ure or bu~ers.
The pharma~e~ti~al preparation can be in solid
~orm, e.~., as tablet~, coated tabl~ts, suppo~itories,
oap~ules or in liguid form, e.g., a~ solutlon3,
su~pen~ions or emul~ions.
The dosage o~ t~e active ingredient~ can vary
according to the method of admini~trati~n, acJe and weigh~
of th~ pa~iRnt, type ~nd ~bverlty oP the ~i~Qase to be
tr~a~ed ~nd ~imilar faators. The daily dose i3 O. 001-
0.034 mg, and th~ dvse ~an be g~Ven ~ an individual dose
t~ be admini~tere~ ona~ or divided into 2 or more daily
dose~.
.
I
~a3:~33
For the above-de~cri~ed s~ t:alloe ~ype~, th~
~ollowing pr~ferred 1ndividual dose rang~ with optimum
individu~l do~e (in parenthe~e~) are indl~eds
~1) AP-7 : 10 - ~00 (150) mg
CPP : 1 - 250 (~5) mg
CGS 1~755 : 0.1 - 100 ~10) m~
~2) ~K-801 : 0~1 - 100 (1~ ~g
Meman~in~- : 10 - 1000 (100) mg
K~tamine : 10 - 750 (100) mg
I~enprodil : U~ 100 (10) m~
(3~ Kynurenic ~id : 100 - 5000 (50~) mg
HA ~66 : 0.01 - ~OD (5) mg
~4~ Polya~lne antagoni~t~ : 100 - S~OO (500) my
(spermine/~permidin~
~5~ Bip~riden : 0.1 - 50 ~2~ mg
trih~xiph~nidyl
(6) EA2~ synthe~i8 : 0.1 - 50 (2) m~
inhi~ito~
The 6ub~t~naes used aco~rding to the invent:ion ~an
optionally be u~ed with o~her u~ually u~e~ pharmaceutical
ay~nt~ with an~ arkinson~ disea~e actiQn ~U~h as L~
dopa. ~y combina~loh ~ th~ ph~rma~eu~ical ag~n~6
according to the invention with th~ usual dopamin~-
in~r~ing anti-ParkinRon~ disease ~ents the dose o~
the usual pharmaceutical agent to be administered iB
reduced .
