WO1989007098A1 - Spermine de butyrl-tyrosinyle, analogues d'une telle spermine et procede de preparation et d'utilisation d'une telle spermine - Google Patents

Spermine de butyrl-tyrosinyle, analogues d'une telle spermine et procede de preparation et d'utilisation d'une telle spermine Download PDF

Info

Publication number
WO1989007098A1
WO1989007098A1 PCT/US1989/000482 US8900482W WO8907098A1 WO 1989007098 A1 WO1989007098 A1 WO 1989007098A1 US 8900482 W US8900482 W US 8900482W WO 8907098 A1 WO8907098 A1 WO 8907098A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
receptor
glutamate
binding
hydrogen
Prior art date
Application number
PCT/US1989/000482
Other languages
English (en)
Inventor
Koji Nakanishi
Amira T. Eldefrawi
Mohyee E. Eldefrawi
Peter N. R. Usherwood
Original Assignee
The Trustees Of Columbia University In The City Of
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by The Trustees Of Columbia University In The City Of filed Critical The Trustees Of Columbia University In The City Of
Publication of WO1989007098A1 publication Critical patent/WO1989007098A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • A01N37/46—N-acyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
    • C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C245/18—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/16—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/16—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C247/18—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • Glutamate receptors are believed to be the principal excitatory neurotransmitter receptors in the mammalian brain. Based on the chemicals that activate glutamate receptors, such receptors are generally divided into three major subtypes: quisqualate, N-methyl-D-aspartate (NMDA), and kainate. These receptors are involved in development, learning and neuropathology and likely mediate the neurodegenerative consequences of hypoxemia, status epilepticus and Huntington's disease (Cotman, C.W. and Iversen, L.L., Trends Neurosci. 1987, 10:263-265; Robinson, M.B.
  • NMDA receptors are involved in a variety of neurological and psychiatric disorders, and antagonists of this receptor may be therapeutically valuable in movement disorders, such as epilepsy, and in various acute and chronic neurodegenerative disorders.
  • the solitary digger wasp Philanthus triangulum F., which is a sphecid wasp that preys on honey bees, manufactures a venom which blocks glutamate receptors on locust skeletal muscle (Piek, T., et al. (1971); Piek, T., et al. (1975)).
  • the present invention concerns the active ingredient contained in venom from the wasp Philanthus triangulum F., the chemical structure of this active ingredient, a method for synthesizing the ingredient. designated philanthotoxin-433 (PTX-433), and the use of PTX-433 as a potent inhibitor of the glutamate receptors.
  • the present application describes the synthesis of pharmacologically active analogs of this ingredient, e.g. PTX-334 and PTX-343 wherein the numerals denote the number of methylenes between the amino groups of the spermine moiety.
  • the present invention concerns a compound having the structure:
  • R 1 is a branched- or unbranched-chain alkylamine having from 2 to 20 atoms in the chain and wherein each of R 2 , R 3 and R 4 is the same or different and is hydrogen or a C 1 to C 20 alkyl, alkenyl, alkynyl, or alkenynyl group.
  • R 1 is:
  • the invention also concerns a method of preparing the compound which comprises treating venom, venom sacs or venom glands or the wasp Philanthus triangulun F. to produce a aqueous extract, and recovering the compound from the resulting aqueous extract. Additionally, the invention provides a method of preparing the compound which comprises contacting a branched- or unbranchedchain alkylamine having from two to twenty atoms in the chain and having hydrogen or a protection group attached to each nitrogen atom of the chain with a compound having the structure:
  • R 3 and R 4 are defined previously, so as to form a product, treating the product to produce the compound and recovering the compound.
  • Another aspect of the invention concerns a method of treating a subject afflicted by a disorder associated with binding of an etiological agent to a glutamate receptor which comprises administering to the subject an amount of the compound effective to inhibit binding of the etiological agent to the receptor.
  • the invention also concerns a method of treating a subject afflicted by a stroke-related disorder associated with excessive binding of glutamate to glutamate receptors which comprises administering to the subject an amount of. the compound effective to inhibit the excessive binding of the glutamate to the receptors.
  • the invention provides an insecticidal composition which comprises a effective amount of the compound and a suitable carrier and a method of combatting insects which comprises administering to the insects an amount of the insecticidal composition effective to produce paralysis in the insects.
  • Fig. 2- Fractionation of Philanthus venom by reverse phase high pressure liquid chromatography (HPLC).
  • A Fractionation of lyophilyzed venom glands, extracted in 50% acetonitrile/water. 450 ⁇ l (representing extracts of 225 wasps) were chromatographed on a YMC-ODS 20x280 mm column and developed by a linear gradient of 5% CH 3 CN/0.1% TFA-95% CH 3 CN/0.1% TFA for 30 min at a flow rate of 8 ml/min. UV absorption was monitored at 215 nm.
  • B Fractionation of main toxic fraction (hatched peak in Fig 2A).
  • Fig. 3- The chemical structures and synthesis of the natural philanthotoxin (PTX-433) and two isomers PTX-334 and PTX-343.
  • A The structures of the three toxins.
  • B Synthesis of intermediates of compounds 1 and 2.
  • C The final steps in synthesis of the three toxins.
  • A) and (B) are data from different nerve-muscle preparations dissected from the same adult, female locust (Schistocerca gregaria). The nerve-muscle preparations were superfused with standard locust saline (23) for 30 min before the toxins were applied.
  • the retractor unguis nerve was stimulated with single, brief (0.1 s), supramaximal stimuli applied at a constant, low frequency, before and after toxin application (in locust saline), but during the period of toxin application the stimulation frequency was sometimes reversed temporarily.
  • the invention concerns a compound having the structure:
  • R 1 is a branched- or unbranched- chain alkylamine having from 2 to 20 atoms in the chain and wherein each of R 2 , R 3 and R 4 is the same or different and is hydrogen or a C 1 to C 20 alkyl, alkenyl, alkynyl, or alkenynyl group.
  • a branched-chain alkylamine is contemplated to be an alkylamine having lower (e.g. C 1 to C 20 ) alkyl groups attached to one or more of the atoms in the chain.
  • the alkylamine is unbranched and has up to three nitrogen atoms and up to fifteen carbon atoms in the chain.
  • R 2 and R 3 are the same and are hydrogen, while R 4 is a lower alkyl group, particularly -CH 2 CH 2 CH 3 .
  • R 1 is an alkylamine having 3 nitrogen atoms and 10 carbon atoms connected in a chain.
  • R 1 may have the structure:
  • the invention also provides a method of preparing or isolating the compound:
  • R 2 and R 3 are hydrogen, R 4 is -CH 2 CH 2 CH 3 and R 1 is an unbranched alkylamine having up to three nitrogen atoms and up to fifteen carbon atoms in the chain, preferably having the structure:
  • the method comprises treating venom, venom sacs or venom glands or the wasp Philanthus triangulum F. to produce an aqueous extract, and recovering the compound from the resulting aqueous extract.
  • the recovering may be effected by a variety of separation techniques known to those skilled in the art to which the invention pertains, such as filtration, centrifugation, and chomotography.
  • An especially preferred recovery method is high pressure liquid chomotography.
  • the treating of the venom, venom sacs, or venom glands may be effective by extraction with numerous organic solvents, such as 50% CH 3 CN-H 2 O. Preferably, a series of extractions is performed wherein each subsequent extraction is performed on the fraction resulting from the previous extraction.
  • the invention also provides a method of synthesizing the compound described hereinabove which comprises contacting a branched- or unbranched-chain alkylamine, having from two to twenty atoms in the chain and having hydrogen or a protection group attached to each nitrogen atom of the chain, with a compound having the structure:
  • R 3 and R 4 are previously defined, so as to form a product, treating the product to produce the compound and recovering the compound.
  • the treating of the product may comprise deprotection with trifluoroacetic acid or hydrogen.
  • the alkylamine has the formula:
  • each of x, y, z is the same or different and is an integer from 1 to 6 and each of R 5 , R 6 and R 7 is the same or different and is hydrogen or a protection group.
  • protection groups may be used in the practice of the present invention and these protection groups are well-known to those skilled in art to which the invention pertains. Examples of useful protection groups include tert-butoxycarbonyl and carbobenzoxy groups and derivatives thereof.
  • the alkylamine has the structure:
  • Boc is a tert-butoxycarbonyl group and Cbz is a carbobenzoxy group.
  • Such an alkylamine may be obtained by contacting acylonitrile with a spermidine derivative having the structure:
  • the alkylamine has the structure:
  • the compound of the present invention may also be radioactively labeled or be formulated into a pharmaceutical composition or an insecticidal composition comprising an effective amount of the compound and a suitable carrier.
  • the compound may also be mixed with glutamate to form an admixture which in turn may be mixed with a carrier to provide a pharmaceutical composition.
  • the compound may also be useful as an anticonvulsant.
  • Another aspect of the invention concerns a method of inhibiting binding to a glutamate receptor which comprises contacting the receptor with a binding-inhibiting amount of the compound described hereinabove or the admixture of the compound with glutamate.
  • Such methods of inhibiting binding to glutamate receptors may prove useful in medical applications, agricultural applications or as research tools for the study of humans and animals.
  • the invention provides a method of treating a subject afflicted by a disorder associated with binding of an etiological agent to a glutamate receptor which comprises administering to the subject an amount of the compound or the admixture effective to inhibit binding of the etiological agent to the receptor.
  • the method is particularly useful where the receptor is a quisqualate or NMDA receptor.
  • the present invention may have therapeutic value in epilepsy, in movement disorders, in protection from ischemic brain damage and in various neurodegenerative disorders.
  • the method may be useful where the neurodegenerative disorder is Huntington's disease, Parkinson's disease or Alzheimer's disease.
  • Another embodiment provides a method of treating a subject afflicted by a strokerelated disorder associated with excessive binding of glutamate to glutamate receptors which comprises administering to the subject an amount of the compound or admixture effective to inhibit the excessive binding of the glutamate to the receptors.
  • the compound may be mixed with a suitable carrier to form an insecticidal composition and the insecticidal composition may be used in a method of combating insects which comprising administering to the insects an amount of the insecticidal composition effective to induce paralysis in the insects.
  • Honey bee workers (1-3 weeks old) were restrained by chilling at 4oC then placed on their backs in a leucite holder (16 bees to a holder) and injected in the ventral thorax behind the first pair of legs with 1 ⁇ l of water extract of the venom glands and immediately transferred to holding cages supplied with 40% sucrose solution. Controls received phosphate buffered Ringer.
  • the metathoracic retractor unguis nerve-muscle preparation of the locust Schistocerca gregaria was dissected and mounted in a small Preapex bath as described previously (Usherwood, P.N.R. and Machili, P., J. Exp. Biol., 1968, 49:341-361).
  • the muscle apodeme was attached to a Grass FT 10 strain gauge with a short strand of terylene and the muscle stretched to maximal body length.
  • the total volume of the bath, including inlet and outlet reservoirs, was about 2.2 ml and the contents could be replaced within 1 sec.
  • the dissection and setting up procedure were performed in continuously flowing saline.
  • the muscle was stimulated indirectly through fine (40-80 ⁇ ) platinum wire electrode, insulated to its tip and placed on the retractor unguis nerve.
  • the venom fractions were dissolved in locust saline of the following composition: NaCl, 140 mM; KCl, 10 mM; CaCl 2 , 2mM; NaH 2 PO 4 , 4mM; Na 2 HPO 4 , 6 mM, and buffered at pH 6.8.
  • the nerve muscle preparation was perfused with this saline at a flow rate of 5-10 ml/min at 19oC.
  • the extract of each batch of 1000 venom glands was fractionated by reverse-phase HPLC and 30 fractions collected. Each of the 30 fractions was tested for pharmacological activity on the locust nerve muscle preparation, using reduction in neurally evoked twitch applitude as the measure of activity. Ten fractions were pharmacologically active. The most active fraction was the one collected at retention time 13 min (hatched peak in Fig. 2A). Further purification of this fraction by reverse-phase HPLC gave four peaks (Fig. 2B), the most pharmacologically active was in the major peak (hatched Fig. 2B). This fraction gave 1.1 mg of toxin as amorphus powder.
  • Figs. 3B and C Chemical synthesis of the three isomers is illustrated in Figs. 3B and C.
  • the protected polyamine 6 was obtained from spermidine derivative 4 (Humora, M. and Quick, J., Org. Chem., 1970, 44: 1166-1168) through Fig. 3B: (1) Michael addition to acrylonitrile (76%); (2) Boc-protection (81%); and (3) reduction of the nitrile (70%). Further Cbz-protection and Boc-deprotection of 6 yielded partially protected polyamine 7 (Boc represents tert-butoxycarbonyl and Cbz represents carbobenzoxy).
  • PTX-433 and analogs PTX-334 and PTX-343 represent a new class of chemicals that are active biologically and inhibit allosterically the quisqualate-sensitive glutamate receptor in insect skeletal muscle (Fig. 4). They are smaller in molecular weight (435 daltons) than the toxins isolated from orb web spider venoms, the argiotoxins (>600 daltons) and easier to synthesize.
  • Binding PTX-433 to NMDA Receptor The NMDA receptor is identified by its high affinity for the compound (+)-5- methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10 imine maleate (MK-801). This compound is an anticonvulsant introduced by Merck Sharp & Dohme Co. and is a potent non-competitive antagonist of the NMDA receptor. Binding of [ 3 H]MK-801 to synaptic membranes from rat brain after thorough washing is extremely poor.
  • the binding is potentiated by glutamate in a dose-dependent manner and reaches maximal potentiation at 10 ⁇ M glutamate (Foster and Wong, Brit. J. Pharmacol. 91, 403 (1987)).
  • the increase m binding of [ 3 H]MK-801 resulting from addition of glutamate has been used as an index of NMDA receptor binding.
  • Philanthotoxin (PTX433) inhibited the binding of [ 3 H]MK-801 to NMDA receptors (Fig. 1) with an EC 50 (the concentration that inhibits 50% of binding) of 25 ⁇ M.
  • MK-801 and PTX-433 may affect the NMDA receptor by binding to distinct allosteric sites on the receptor protein.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention se rapporte à un composé représenté par la structure: (I), où R1 représente une alkylamine à chaîne ramifiée ou non-ramifiée comportant 2 à 20 atomes dans la chaîne et où R2, R3 et R4 sont chacun identiques ou différents et représentent de l'hydrogène ou un groupe alkyle, alkényle, alkynyle ou alkénynyle de 1 à 20 atomes de carbone. La présente invention se rapporte également à un procédé de préparation dudit composé à partir du venin, des sacs ou des glandes venimeuses de la guêpe (Philanthus triangulum F.). La présente invention décrit en outre un procédé de synthèse chimique dudit composé. Un autre aspect de la présente invention se rapporte à un procédé de traitement d'un sujet atteint d'un désordre associé à la liaison d'un agent étiologique avec un récepteur de glutamate. La présente invention décrit enfin une composition insecticide contenant une quantité efficace dudit composé et un procédé de lutte contre les insectes qui consiste à administrer aux insectes ladite composition insecticide.
PCT/US1989/000482 1988-02-08 1989-02-07 Spermine de butyrl-tyrosinyle, analogues d'une telle spermine et procede de preparation et d'utilisation d'une telle spermine WO1989007098A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15315188A 1988-02-08 1988-02-08
US153,151 1988-02-08

Publications (1)

Publication Number Publication Date
WO1989007098A1 true WO1989007098A1 (fr) 1989-08-10

Family

ID=22545978

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1989/000482 WO1989007098A1 (fr) 1988-02-08 1989-02-07 Spermine de butyrl-tyrosinyle, analogues d'une telle spermine et procede de preparation et d'utilisation d'une telle spermine

Country Status (1)

Country Link
WO (1) WO1989007098A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434173A2 (fr) * 1989-12-04 1991-06-26 Schering Aktiengesellschaft Emploi des antagonistes des récepteurs NMDA dans le traitement des maladies neurodégénératives chroniques
US5622981A (en) * 1993-06-01 1997-04-22 Cortex Pharmaceuticals, Inc. Use of metabotropic receptor agonists in progressive neurodegenerative diseases
WO2002016314A1 (fr) * 2000-08-18 2002-02-28 H. Lundbeck A/S Composes polyamines substitues

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888898A (en) * 1935-11-15 1975-06-10 Boehringer Sohn Ingelheim N,n'-bis-(3-phenoxy-2-hydroxy-propyl)-alkenediamines and salts thereof
US4533655A (en) * 1981-07-24 1985-08-06 Sterling Drug Inc. Analgesic dipeptide amides and method of use and compositions thereof
EP0156540A1 (fr) * 1984-03-02 1985-10-02 Takeda Chemical Industries, Ltd. Un inhibiteur pour récepteur de glutamate
EP0174085A2 (fr) * 1984-07-26 1986-03-12 BEECHAM - WUELFING GmbH & Co. KG Bisarylamides de N,N'-di-[1-aminoalkyl-2]-alkylène diamines avec une activité cardio-vasculaire
US4719288A (en) * 1983-11-23 1988-01-12 Ciba-Geigy Corporation Substituted 5-amino-4-hydroxyvaleryl derivatives
US4760180A (en) * 1986-02-14 1988-07-26 G. D. Searle & Co. N-terminally substituted dipeptide amides

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888898A (en) * 1935-11-15 1975-06-10 Boehringer Sohn Ingelheim N,n'-bis-(3-phenoxy-2-hydroxy-propyl)-alkenediamines and salts thereof
US4533655A (en) * 1981-07-24 1985-08-06 Sterling Drug Inc. Analgesic dipeptide amides and method of use and compositions thereof
US4719288A (en) * 1983-11-23 1988-01-12 Ciba-Geigy Corporation Substituted 5-amino-4-hydroxyvaleryl derivatives
EP0156540A1 (fr) * 1984-03-02 1985-10-02 Takeda Chemical Industries, Ltd. Un inhibiteur pour récepteur de glutamate
EP0174085A2 (fr) * 1984-07-26 1986-03-12 BEECHAM - WUELFING GmbH & Co. KG Bisarylamides de N,N'-di-[1-aminoalkyl-2]-alkylène diamines avec une activité cardio-vasculaire
US4760180A (en) * 1986-02-14 1988-07-26 G. D. Searle & Co. N-terminally substituted dipeptide amides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KITS, K.S. et al., NEUROPHARMACOLOGY, Vol. 25, No. 10, pages 1089-1093, issued 1986. *
PIEK, T. et al., "Philanthotoxins, Review of the Diversity of action on Synaptic Transmission", PESTICIDE SCIENCE 16(5), issued 1985, pages 488-494. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434173A2 (fr) * 1989-12-04 1991-06-26 Schering Aktiengesellschaft Emploi des antagonistes des récepteurs NMDA dans le traitement des maladies neurodégénératives chroniques
EP0434173A3 (en) * 1989-12-04 1992-01-29 Schering Aktiengesellschaft Berlin Und Bergkamen Use of nmda receptor antagonists for treatment of chronic neurodegenerative diseases
US5622981A (en) * 1993-06-01 1997-04-22 Cortex Pharmaceuticals, Inc. Use of metabotropic receptor agonists in progressive neurodegenerative diseases
WO2002016314A1 (fr) * 2000-08-18 2002-02-28 H. Lundbeck A/S Composes polyamines substitues

Similar Documents

Publication Publication Date Title
Eldefrawi et al. Structure and synthesis of a potent glutamate receptor antagonist in wasp venom.
DE3889756T2 (de) Benzodiazepin-Analoge.
DE69725153T2 (de) Kaliumkanal-blocker
Bruce et al. Structure-activity relationships of analogues of the wasp toxin philanthotoxin: non-competitive antagonists of quisqualate receptors
DE69416501T2 (de) 2-propylvaleriansäure und 2-propylvalerian-säureamid-derivate und deren verwendung als antikonvulsive mittel
US5242947A (en) Use of polyamines as ionic-channel regulating agents
DE69233572T2 (de) Screening-Verfahren für Kalzium-Rezeptor aktive Verbindungen
DE69532645T2 (de) Heterozyklische pentapeptitische und halophenyl amide als hemmer für menschlichen krebs
DE69627852T2 (de) Verbindungen, die an einer neuen stelle auf rezeptor-stimulierten kalziumkanälen wirksam sind, verwendbar zur behandlung von neurologischen krankheiten
DE69024253T2 (de) Polyamine, verwendbar als Antagonisten von durch Aminosäuren anregbaren Neurotransmittern und/oder als Blocker von Calciumkanälen
EP0646595A1 (fr) Oligomères liant les acides nucléiques avec branchement en C pour thérapie en diagnostic
DE3177306T2 (de) Verfahren und Verbindungen zur Herstellung von H-ARG-X-Z-Y-TYR-R.
DE69313650T2 (de) Calcium-kanal blockierende polypeptide aus agelenopsis aperta
EP0733036A1 (fr) Alpha-aminoacides alpha quaternaires utilises comme agents influant sur le snc (systeme nerveux central)
WO1996022962A9 (fr) Butyryl-tyrosinyl spermine, ses analogues et leurs procedes de preparation et d'utilisation
WO1996022962A1 (fr) Butyryl-tyrosinyl spermine, ses analogues et leurs procedes de preparation et d'utilisation
Lunn et al. DL-tetrazol-5-ylglycine, a highly potent NMDA agonist: its synthesis and NMDA receptor efficacy
DE60133654T2 (de) Arzneimittel enthaltend analgetische peptide
DE69007739T2 (de) Polypeptide verwertbar als Kalziumkanälen-Blocker.
DE69431050T2 (de) PYRIDO[2,3-b](1,4)BENZODIAZEPINONE ALS M2-REZEPTORLIGAND ZUR BEHANDLUNG NEUROLOGISCHER STÖRUNGEN
JP2003508512A (ja) 非ペプチド性サイクロフィリン結合化合物とその用途
WO1989007098A1 (fr) Spermine de butyrl-tyrosinyle, analogues d'une telle spermine et procede de preparation et d'utilisation d'une telle spermine
DE69732143T2 (de) Mit einem glycintransporter transfizierte zellen und deren anwendungen
RU2128650C1 (ru) (S)-α-ФЕНИЛ-2-ПИРИДИНЭТАНАМИН И ЕГО СОЛЬ С НЕОРГАНИЧЕСКИМИ КИСЛОТАМИ, СПОСОБ ИХ ПОЛУЧЕНИЯ, ЛЕКАРСТВЕННЫЙ ПРЕПАРАТ НА ИХ ОСНОВЕ И СПОСОБ ЛЕЧЕНИЯ СУДОРОГ
US5770625A (en) Butyryl-tyrosinyl spermine, analogs thereof and methods of preparing and using same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE