CA2031433A1 - Use of nmda receptor antagonists - Google Patents
Use of nmda receptor antagonistsInfo
- Publication number
- CA2031433A1 CA2031433A1 CA002031433A CA2031433A CA2031433A1 CA 2031433 A1 CA2031433 A1 CA 2031433A1 CA 002031433 A CA002031433 A CA 002031433A CA 2031433 A CA2031433 A CA 2031433A CA 2031433 A1 CA2031433 A1 CA 2031433A1
- Authority
- CA
- Canada
- Prior art keywords
- antagonist
- disease
- degeneration
- neurons
- nmda receptor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Abstract
ABSTRACT OF THE DISCLOSURE
The new use of antagonists of the N-methyl-D-aspertate (NMDA) receptor complex or their physiologically compatible salts as pharmaceutical agents for prevention of chronic neurodegenerative disease, as well as pharmaceutical agents, which contain these compounds, are described.
The new use of antagonists of the N-methyl-D-aspertate (NMDA) receptor complex or their physiologically compatible salts as pharmaceutical agents for prevention of chronic neurodegenerative disease, as well as pharmaceutical agents, which contain these compounds, are described.
Description
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
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
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 .
(~) 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 .
Claims (14)
1. A method for the prevention or treatment of a chronic neurodegenrative disease, comprising administering to a host an effective amount of an NMDA
receptor complex antagonist or a physiologically compatible salt thereof.
receptor complex antagonist or a physiologically compatible salt thereof.
2. A method of claim 1, wherein the antagonist is a competitive antagonist.
3. A method of claim 2, wherein the antagonist is 2-amino-7-phosphonoheptanoic acid, 3-((+)2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid or cis-4-phosphonomethyl-2-piperidine carboxylic acid.
4. A method of claim 1, wherein the antagonist is a con-competitive antagonist.
5. A method of claim 4, wherein the antagonist is (+)10,11-dihydro-5-methyl-5H-dibenzo-[a,d]-cyclohepten-5,10-imine, memantine, amantadine, ketamine or ifenprodil.
6. A method of claim 4, where the antagonist is one which acts on glycine binding sites.
7. A method of claim 6, wherein the antagonist is kynurenic acid or l-hydroxy-3-amino-pyrrolidin-2-one.
8. A method of claim 4, wherein the antagonist is a polyamine.
9. A method of claim 8, wherein the polyamine is spermine or spermidine.
10. A method of claim 1, wherein the antagonist is an anticholinergic agent.
11. A method of claim 10, wherein the agent is biperiden or trihexiphenidyl.
12. A method of claim 1, wherein the disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or olivo[ontocerebellar degeneration.
13. A method according to claim 1, wherein degeneration triggered by (MPP) is inhibited.
14. A method for the prevention or lessening of degeneration of dopaminergic neurons, cholinergic neurons, cortical motor neurons or spinal motor neurons, comprising administering to a host an effective amount of an NMDA receptor-complex antagonist.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3940410.2 | 1989-12-04 | ||
| DE3940410A DE3940410A1 (en) | 1989-12-04 | 1989-12-04 | NEW USE OF NMDA RECEPTOR ANTAGONISTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2031433A1 true CA2031433A1 (en) | 1991-06-05 |
Family
ID=6394957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002031433A Abandoned CA2031433A1 (en) | 1989-12-04 | 1990-12-04 | Use of nmda receptor antagonists |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0434173A3 (en) |
| JP (1) | JPH03209335A (en) |
| CA (1) | CA2031433A1 (en) |
| DE (1) | DE3940410A1 (en) |
| IE (1) | IE904360A1 (en) |
| PT (1) | PT96074A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6562836B1 (en) | 1999-05-24 | 2003-05-13 | Queen's University Of Kingston | Methods and compounds for inhibiting amyloid deposits |
| US7244764B2 (en) | 2003-06-23 | 2007-07-17 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US7414076B2 (en) | 2003-06-23 | 2008-08-19 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US8044100B2 (en) | 2004-12-22 | 2011-10-25 | Bellus Health Inc. | Methods and compositions for treating amyloid-related diseases |
| US8642801B2 (en) | 2003-06-23 | 2014-02-04 | Bhi Limited Partnership | Methods and compositions for treating amyloid-related diseases |
| US9499480B2 (en) | 2006-10-12 | 2016-11-22 | Bhi Limited Partnership | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5334618A (en) * | 1991-04-04 | 1994-08-02 | The Children's Medical Center Corporation | Method of preventing NMDA receptor-mediated neuronal damage |
| DE4118740A1 (en) * | 1991-06-05 | 1992-12-10 | Schering Ag | NEW COMBINATION DEVICES FOR TREATING MORBUS PARKINSON |
| GB9209599D0 (en) * | 1992-05-02 | 1992-06-17 | Fisons Corp | Novel therapy for the treatment of parkinsons disease |
| EP1014994A1 (en) * | 1997-08-18 | 2000-07-05 | Queen's University At Kingston | Phosphono-carboxylate compounds for treating amyloidosis |
| AU3822902A (en) * | 1997-08-18 | 2002-06-27 | Queen's University At Kingston | Phosphono-carboxylate compounds for treating amyloidosis |
| US6329356B1 (en) | 1998-04-10 | 2001-12-11 | Neurochem, Inc. | Phosphono-carboxylate compounds for treating amyloidosis |
| EP1448183A2 (en) * | 2001-11-16 | 2004-08-25 | ALS Therapy Development Foundation, Inc. | Treatment of neurodegenerative disorders through the modulation of the polyamine pathway |
| US7211602B2 (en) | 2001-11-16 | 2007-05-01 | Als Therapy Development Foundation, Inc. | Treatment of neurodegenerative disorders through the modulation of the polyamine pathway |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8625941D0 (en) * | 1986-10-30 | 1986-12-03 | Sandoz Ltd | Substituted alpha-amino acids |
| WO1989007098A1 (en) * | 1988-02-08 | 1989-08-10 | The Trustees Of Columbia University In The City Of | Butyrl-tyrosinyl spermine, analogs thereof and methods of preparing and using same |
-
1989
- 1989-12-04 DE DE3940410A patent/DE3940410A1/en not_active Withdrawn
-
1990
- 1990-11-20 JP JP2312981A patent/JPH03209335A/en active Pending
- 1990-12-04 EP EP19900250303 patent/EP0434173A3/en not_active Withdrawn
- 1990-12-04 CA CA002031433A patent/CA2031433A1/en not_active Abandoned
- 1990-12-04 PT PT96074A patent/PT96074A/en not_active Application Discontinuation
- 1990-12-04 IE IE436090A patent/IE904360A1/en unknown
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6562836B1 (en) | 1999-05-24 | 2003-05-13 | Queen's University Of Kingston | Methods and compounds for inhibiting amyloid deposits |
| US7393875B2 (en) | 1999-05-24 | 2008-07-01 | Neurochem (International) Limited | Methods and compounds for inhibiting amyloid deposits |
| US7244764B2 (en) | 2003-06-23 | 2007-07-17 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US7414076B2 (en) | 2003-06-23 | 2008-08-19 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US8642801B2 (en) | 2003-06-23 | 2014-02-04 | Bhi Limited Partnership | Methods and compositions for treating amyloid-related diseases |
| US8044100B2 (en) | 2004-12-22 | 2011-10-25 | Bellus Health Inc. | Methods and compositions for treating amyloid-related diseases |
| US8835654B2 (en) | 2004-12-22 | 2014-09-16 | Bhi Limited Partnership | Method and compositions for treating amyloid-related diseases |
| US9499480B2 (en) | 2006-10-12 | 2016-11-22 | Bhi Limited Partnership | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
| US10238611B2 (en) | 2006-10-12 | 2019-03-26 | Bellus Health Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
| US10857109B2 (en) | 2006-10-12 | 2020-12-08 | Bellus Health, Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
| US11020360B2 (en) | 2006-10-12 | 2021-06-01 | Bellus Health Inc. | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0434173A3 (en) | 1992-01-29 |
| JPH03209335A (en) | 1991-09-12 |
| PT96074A (en) | 1991-09-30 |
| IE904360A1 (en) | 1991-06-05 |
| EP0434173A2 (en) | 1991-06-26 |
| DE3940410A1 (en) | 1991-06-06 |
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