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WO1991002523A1 - Agonistes et antagonistes de l'amino acide glutamatergique - Google Patents

Agonistes et antagonistes de l'amino acide glutamatergique Download PDF

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Publication number
WO1991002523A1
WO1991002523A1 PCT/US1990/004647 US9004647W WO9102523A1 WO 1991002523 A1 WO1991002523 A1 WO 1991002523A1 US 9004647 W US9004647 W US 9004647W WO 9102523 A1 WO9102523 A1 WO 9102523A1
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Prior art keywords
amino acid
sch
och
electronegative group
topa
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PCT/US1990/004647
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English (en)
Inventor
Paul A. Rosenberg
Elias Aizenman
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Boston Childrens Hospital
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Boston Childrens Hospital
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group

Definitions

  • This invention concerns amino acids, and methods of their use, which protect a neuron of a human patient from injury, especially injury caused by the presence of excess glutamate or related compounds.
  • Glutamate is known to be an excitatory amino acid (causing depolarization and action potential generation when applied to neurons of the central nervous system) with efficacy at at least three subtypes of excitatory amino acid receptors, namely kainate, quisqualate, and N-methyl-D-aspartate (NMDA). It is present at high
  • Glutamate or compounds that act like glutamate are thought to play a role in neuronal injury, and to mediate a variety of brain insults, including ischemia, hypoxia, and physical trauma.
  • a role for glutamate or glutamate agonists has been postulated in Alzheimer's disease, Parkinson's disease, and Huntington's disease.
  • glutamate antagonists compounds that block the action of glutamate or glutamate agonists
  • antagonist is meant a compound which counteracts the effect of an agonist, i.e., it opposes the action on a nerve cell of an agonist. Implicit in the concept of agonist and antagonist action is interaction of these substances at a specific
  • Agonists bind to specific receptor sites and this interaction results in a measurable response.
  • Antagonists bind to the same site, and are capable of displacing agonists and preventing the occurrence of the associated response.
  • Choi U.S. Patent 4,806,543, describes a method for reducing adverse effects of neurotoxic injury by administering an enantiomer of an analgesic opioid agonist or antagonist. Such compounds are said to be useful for treatment of any animal species having NMDA receptors.
  • PCP phencyclidine
  • the invention features a nerve cell medium composition containing an effective dose of an agonist or antagonist of a glutamate receptor, effective to act as an agonist or antagonist on a nerve cell or of neuronal injury, chosen from an amino acid having the following chemical structure:
  • each R 1 , R 2 , R 3 R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , and R 12 is independently an electronegative group, H, CH 3 , SCH 3 , NH 2 or OCH 3 ; and R 7 is an electronegative group.
  • nerve cell medium composition is meant a buffer or vehicle which is compatible with nerve cell survival in vitro, e.g., physiological saline.
  • each electronegative group is separately selected from OH, N 2 O, CN, SO 3 H, Cl, F, Br, I, and CO 2 H;
  • A is:
  • each R group is independently CH 2 , SCH 3 , OCH 3 or H;
  • A is
  • R 1 and R 3 are independently H, CH 3 , OCH 3 or SCH 3 and R is H, CH 3 , SCH 3 , OCH 3 or an electronegative group;
  • A is:
  • R 4 and R 6 group are independently SCH 3 , CH 3 , OCH 3 or H, and R 5 is SCH 3 , CH 3 , OCH 3 , H or an electronegative group; most preferably R 4 and R 6 are each H and R 5 is H or a halogen; and A is:
  • R 7 is an electronegative group, most preferably CN or a halogen.
  • the invention features a pharmaceutically acceptable composition including an effective dose of an antagonist of a glutamate receptor, effective to act as an antagonist of neuronal injury, e.g., toxicity, or death, chosen from the above described amino acids.
  • the antagonist is admixed with a suitable buffer.
  • the invention features a method for identifying an amino acid antagonist useful for protection of a neuron of an organism from injury.
  • the method includes providing a cell having a glutamate receptor, selecting an amino acid from those described above, treating the cell with the amino acid, and
  • the amino acid acts as an antagonist at the receptor, e.g., coapplying the amino acid with a known agonist.
  • amino acid is able to either totally reverse, or at least. partially reverse, the effect of a toxic agonist on that neuron, e.g., kainate or
  • the amino acid is able oo r.educe the effect of glutamate on the neuron, and thereby significantly increase the chances of that neuron
  • organism is intended to include any animal to which an amino acid of the invention can be administered for the indicated purpose, including both medicinal and veterinary purposes. Use in mammals and birds of all types is preferred, with use in humans being a primary utility.
  • the step of determining includes determining the electrophysiological response of the cell to the amino acid, with or without the amino acid; or determining the survival of the cell after exposure to the amino acid; the survival may be
  • the receptor is chosen from a non-NMDA receptor.
  • the invention features a method for protecting a neuron of a human patient from injury.
  • the method includes identifying a patient susceptible to neuronal injury, providing a
  • pharmacologically acceptable composition including an antagonist of a glutamate receptor, chosen from those listed above, and administering the antagonist to the patient in an amount effective to protect a neuron from injury.
  • Organisms e.g., human patients, susceptible to neuronal injury are identified by any of a number
  • Such patients will include those discussed above which are susceptible to, or suffer from, strokes, anoxia and certain degenerative diseases. They will also include those patients which have no symptoms but are found to have abnormally high levels of glutamate or related compounds in the CNS, and also those who have a genetic predisposition to the development of disease, e.g., Huntington's disease. Those skilled in the art will recognize how to determine, by routine
  • antagonists are also useful in the treatment of diseases which seem to involve central dopamine projections and their target areas, including schizophrenia,
  • Parkinson's disease complications of anti-phychotic drug therapy, Parkinson's disease, and Huntington's disease.
  • the figure is a schematic representation of chemicals produced by oxidation. of topa.
  • the numbers represent the following compounds: 1, tyrosine; 2, dopa; 3, dopamine; 4, dopa quinone; 5, leuko-dopachrome; 6, dopachrome; 7, topa; 8, ortho-quinone of topa; 9, paraquinone of topa.
  • Amino acids useful in this invention are described above. They may be synthesized by any standard
  • topa quinone which acts as an agonist at non-NMDA sites.
  • Topa quinone is a simple and novel prototype for non-NMDA receptor ligands, and may be an endogenous neurotoxin.
  • the above enumerated amino acids are
  • topa quinone variations on the structure of topa quinone. This example is not meant to be limiting to the present invention.
  • solutions of topa results in glutamatergic responses mediated predominantly by non-NMDA receptors.
  • exposure to solutions of topa results in killing of greater than 97% of the neurons in cortical cultures.
  • Topa itself is unstable in aqueous solutions and oxidizes to form the amino acid topa quinone. This compound appears to be the active
  • topa quinone is a compound, rather than topa, at glutamatergic receptors. Details of the effect of topa quinone are now presented.
  • cortical neurons used rat cerebral cortex in dissociated cell culture prepared as follows. Tissue was derived from E16 fetal rats, dissociated using trypsin, and plated on collagen and poly-L-lysine coated glass coverslips. Growth medium was Dulbecco's modified Eagle's medium/Ham's F-12/calf serum 8:1:1 (DHS). Cultures were mitotically inhibited by exposure to 5 ⁇ M cytosine arabinoside for 48 hours starting at 15 days in vitro. and medium was changed three times per week.
  • DHS Dulbecco's modified Eagle's medium/Ham's F-12/calf serum 8:1:1
  • the extracellular solution for the physiological experiments contained (in mM) : NaCl, 137; NaHCO 3 , 1;
  • the intracellular pipette solution contained (in mM) CsCl, 120; TEA-Cl, 20; MgCl 2 , 2; CaCl 2 , 1; EGTA, 1.5-2.25; and HEPES 10, adjusted to pH 7.2 with concentrated NaOH.
  • Drugs were applied by pressure ejection from micropipettes (5 ⁇ M aperture) placed in close proximity (20 ⁇ M) to the cell under study.
  • 10 mM stock solutions of topa (Sigma) were made in 1 mM HC1 and were kept frozen at -80°C.
  • a List EPC-7 patch-clamp amplifier was used, and signals were digitized with a 12-bit 125 kHz analog-to-digital converter (Model DT2782 DMA: Data Translation), and viewed both on an analog oscilloscope and a Hewlett-Packard digital display.
  • the sampling rate was set at 1 to 1.6 kHz and the signals were filtered at 500 Hz.
  • the indifferent Ag/AgCl electrode was connected to the extracellular solution by a 2 M KCl-agarose bridge.
  • Cortical neurons had an input resistance of 0.3 to 0.7 Gohms and a cell capacitance of 20-40 pF. Recordings were performed at 33-35°C. Application of 20-100 ⁇ M topa elicited responses in all neurons tested which reversed in polarity near OmV. Currents activated by application of 50 ⁇ M topa were substantially (>90%) and reversibly blocked by 10-20 ⁇ M 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) , a
  • Perfusion was at a rate of 8ml/min with a physiological saline (130 mM NaCl, 3 mM KCl, 7mM MgCl 2 , 0.1 mM CaCl 2 , 17 mM glucose, 20 mM NaHCO 3 , 0.011 g/L phenol red) bubbled with a gas mixture of 95% O 2 and 5% CO 2 .
  • a physiological saline 130 mM NaCl, 3 mM KCl, 7mM MgCl 2 , 0.1 mM CaCl 2 , 17 mM glucose, 20 mM NaHCO 3 , 0.011 g/L phenol red
  • the DC potential difference between a unipolar suction electrode placed on the cut optic nerve and a unipolar Ag/AgCl electrode placed inside the eyecup solution was amplified 1000X and displayed on an
  • DTT Dithiothreitol
  • DTT appears to affect NMDA but not non-NMDA glutamatergic responses. DTT was found to be an effective agent for preventing the oxidation of topa at a 10:1 molar ratio. The addition of 3mM DTT eliminated the response of the above described eyecup preparation to 300 ⁇ M topa.
  • topa is not topa itself, but rather an oxidation product. Therefore, the active species appears to be one of the oxidation products of topa, shown in the Figure as compounds 6, dopachrome; 8, topa ortho-quinone; or 9, topa para-quinone.
  • Dopachrome was synthesized from dopa using silver oxide (Ag 2 O) Occording to published methods.
  • a solution of 0.5 mg/ml L-dopa in sodium phosphate buffer (50 mM, pH 6.8, passed through a Chelex-100 column) was reacted with Ag 2 O for 3 minutes at 0oC, filtered through a 0.22 ⁇ Millex filter, and batch treated with Chelex-100 to remove Ag ions.
  • the resulting product had no activity in the eyecup preparation experiments described above.
  • topa was used after exposure to silver oxide, using the same method, the product is as potent in the eyecup preparation as spontaneously oxidized topa itself.
  • solutions of dopachrome which are stable for about 30 minutes on ice and thereafter convert from a deep orange-red to a brown color (suggestive of further oxidation)
  • solutions of the oxidation product of topa are much more stable and persist on ice without color change for several hours.
  • the absorbance spectrum of dopachrome, and oxidized topa, in 50 mM sodium phosphate buffer pH 6.8 display a broad absorbance peak centered at approximately 475 nm, and display absorbance peaks in the ultraviolet range, at 306 nm for dopachrome (in agreement with the value previously reported) and at 272 nm for oxidized topa.
  • Topa quinone reacts with ninhydrin, whereas dopachrome did not.
  • topa quinone tautomeric compounds 8 and 9 in the Figure.
  • Rat cerebral cortex in dissociated cell culture was exposed to 500 ⁇ M topa, alone, or in conjunction with 20 ⁇ M CNQX, 20 ⁇ M MK-801, or CNQX plus MK-801. Coverslip cultures were washed once in a
  • physiological saline PS, in mM: NaCl, 145; KCl, 3;
  • coverslips were then placed in wells containing 0.5 ml MEM (no glutamine) with either 500 ⁇ M topa or a vehicle. After 3 hours, experiments were terminated by replacing medium with trypan blue (1:1 dilution with PS), washing once in PS containing 0.01% BSA, and fixing with 2.5% glutaraldehyde in PS.
  • CNQX Tocris Neuramin
  • MK-801 HCl was added from a 2 mM stock in water.
  • Topa was added from a 10 mM stock in 1 mM HCl kept at -80°C.
  • medium containing topa was relaced with MEM after three hours, and cultures were returned to the incubator for 15-20 hours, and were then trypan blue stained and fixed. Cultures treated in this way showed obvious glial toxicity-trypan blue staining of the glial layer starting at the periphery and extending variably toward the center. Few neurons were left in these trypan blue stained areas, even in the presence of CNQX, whereas in areas where the glial layer was not stained, many surviving neurons were present.
  • a three hour exposure to 500 ⁇ M topa produced a large loss of neurons (a mean of 2.7+1.1% neurons
  • topa experiments were performed in which cultures were exposed either to topa (500 ⁇ M) alone or in conjunction with 20 ⁇ M CNQX, 20 ⁇ M MK-801 HCl [(+)-10,11-dihydro-5-methyl-5H-dibenzo- -cycloheptene], or CNQX plus MK-801 together.
  • MK-801 is an NMDA channel blocker and has been shown to block NMDA receptor mediated toxicity in central neurons in culture.
  • CNQX, but not MK-801 produced a significant sparing of neurons exposed to topa.
  • glutamatergic activity of topa indicates that it is useful to determine the presence of this substance, and its breakdown products, in disease states involving dopaminergic areas of the brain, such as Parkinson's disease (both in untreated patients as well as those being treated with L-dopa), Huntington's disease, brain ischemia, as well as schizophrenia.
  • Parkinson's disease both in untreated patients as well as those being treated with L-dopa
  • Huntington's disease both in untreated patients as well as those being treated with L-dopa
  • Huntington's disease both in untreated patients as well as those being treated with L-dopa
  • Huntington's disease both in untreated patients as well as those being treated with L-dopa
  • Huntington's disease both in untreated patients as well as those being treated with L-dopa
  • Huntington's disease both in untreated patients as well as those being treated with L-dopa
  • Huntington's disease both in untreated patients as well as those being treated with L-do
  • amino acids having a chemical structure similar to topa quinone are potentially useful agonists (for in vitro use) or antagonists (for in vivo and in vitro use). These amino acids can be synthesized by standard procedure and screened as described in this application to determine their utility. The tests described above can be used to determine agonist and antagonists activity in vitro, and those described below to determine activity in vivo. Other equivalent tests are well known to those of ordinary skill in this art. Generally, those amino acids which are antagonists at non-NMDA receptors are useful. Amino acids which are antagonists at NMDA receptors are also useful.
  • Thick sections are cut and stained with H & E, and examined for ischemic changes in several regions, including hippocampus, neocortex, and striatum. Special attention is given to the striatum because it is in this structure that a role for dopamine in ischemic injury has been established.
  • mice receive 4 injections of methamphetamine at 2 hr intervals (1-10 mg/kg).
  • drugs are given 15 minutes before and 3 hours after the first injection of methamphetamine. Animals are killed 3 days after treatment. Dopamine and tyrosine hydr ⁇ xylase activity are measured in striata of test animals.
  • amino acids useful in treatment of central neuronal injury such as the acute and chronic neurological diseases of ischemia, hypoxia, hypoglycemia, epilepsy, Parkinson's, Huntington's disease, and Alzheimer's disease.
  • These amino acids generally act to selectably block the
  • amino acids identified above are used in conjunction with other compounds which act at other sites of glutamate receptors.
  • such use will provide synergistic results, in that the level of protection of the neuron from neuronal injury will be greater than the protection provided by either agent alone.
  • lower levels of amino acids, which are identified as useful in the invention can be used in combination with agents which act at other sites.
  • advantageous compositions useful for treatment of the above diseases can be formed by combinations of existing agents, and those amino acids identified by the method of the present invention.
  • Useful amino acids identified by the above methods can be used by standard procedures in treatment of the above mentioned diseases, and related diseases or
  • amino acids are administered to patients susceptible to neuronal injury in an amount of amino acid sufficient to reduce the neuronal injury.
  • administration can be performed on any animal having neuronal glutamate receptors and includes mammals, birds and, in particular, humans.
  • Administration can be by any technique capable of introducing the amino acid into the blood stream of the patient. Once introduced, the amino acids are expected to penetrate the blood-brain barrier. These techniques include oral administration, and intravenous,
  • amino acids of the invention can be formulated into orally administerable forms or pills by standard procedure. Typical doses of the amino acids in
  • pharmaceutically acceptable carriers are from 50 mg to 2 g, and preferably from 100 mg to 1 g. These doses are. suitable for administration to a typical 70 kg human.
  • Administration can, be adjusted to provide the same relative dose per unit of body weight.
  • useful concentrations of the amino acids in the blood stream is the order of 1 to 1000 micromolar, preferably from 1 to
  • amino acids are also useful for in vitro tests, such as for binding studies on rat cortical membranes, study of physiology of rat cortical neurons and chick eyecup preparations (these tests are described above and can be used to discriminate between agonist and antagonist activity), and for toxicity studies.

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Abstract

Composition pour cellules nerveuses, contenant une dose efficace d'un agoniste ou antagoniste d'un récepteur de glutamate, agissant avec efficacité comme agoniste ou antagoniste sur une cellule nerveuse et choisie parmi des acides aminés ayant la structure chimique (I), dans laquelle A est choisie parmi (a), (b), (c) ou (d), chaque R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, et R12 représentent indépendament un groupe électronégatif, H, CH3, SCH3, NH2 ou OCH3; et R7 est un groupe électronégatif.
PCT/US1990/004647 1989-08-17 1990-08-17 Agonistes et antagonistes de l'amino acide glutamatergique Ceased WO1991002523A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5830998A (en) * 1992-09-28 1998-11-03 Maccecchini; Maria-Luisa Allosteric modulators of the NMDA receptor and their use in the treatment of CNS disorders and enhancement of CNS function

Citations (3)

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US3658968A (en) * 1970-06-11 1972-04-25 Merck & Co Inc Composition and method of treatment
US3769424A (en) * 1970-10-01 1973-10-30 Merck & Co Inc Composition and method of treating dopamine deficiency in brain tissue
US4806543A (en) * 1986-11-25 1989-02-21 Board Of Trustees Of The Leland Stanford Junior University Method and compositions for reducing neurotoxic injury

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3658968A (en) * 1970-06-11 1972-04-25 Merck & Co Inc Composition and method of treatment
US3769424A (en) * 1970-10-01 1973-10-30 Merck & Co Inc Composition and method of treating dopamine deficiency in brain tissue
US4806543A (en) * 1986-11-25 1989-02-21 Board Of Trustees Of The Leland Stanford Junior University Method and compositions for reducing neurotoxic injury

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BRIDGES et al., JOURNAL OF NEUROSCIENCE, June 1989, 9(5), 2073-2079. *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5830998A (en) * 1992-09-28 1998-11-03 Maccecchini; Maria-Luisa Allosteric modulators of the NMDA receptor and their use in the treatment of CNS disorders and enhancement of CNS function

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