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WO2012064854A1 - Utilisation d'inhibiteurs du recaptage de la glycine dans la thérapie de la maladie de parkinson - Google Patents

Utilisation d'inhibiteurs du recaptage de la glycine dans la thérapie de la maladie de parkinson Download PDF

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WO2012064854A1
WO2012064854A1 PCT/US2011/059989 US2011059989W WO2012064854A1 WO 2012064854 A1 WO2012064854 A1 WO 2012064854A1 US 2011059989 W US2011059989 W US 2011059989W WO 2012064854 A1 WO2012064854 A1 WO 2012064854A1
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glycine
sprouting
glycine uptake
disease
mice
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David Sulzer
Yvonne Schmitz
Dalibor Sames
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Columbia University in the City of New York
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Columbia University in the City of New York
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0619—Neurons
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • 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
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/80—Neurotransmitters; Neurohormones
    • C12N2501/84—Excitatory amino acids

Definitions

  • the present invention provides methods relating to use of glycine uptake inhibitors for treating Parkinson' s disease (PD) .
  • PD Parkinson' s disease
  • Parkinson's disease is the second most common neurodegenerative disorder, with a life-time incidence of 1- 2%. As it is a disease of older people, it will become increasingly common as life expectancy increases. Parkinson's disease is named after James Parkinson, who was first to describe the disease in his 1817 assay "An Essay on the Shaking Palsy". PD is a chronic progressive neurodegenerative disorder. The symptoms of Parkinson's disease result from the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNpc) region of the brain.
  • SNpc pars compacta
  • the four primary symptoms of PD are 1) tremor, or trembling in hands, arms, legs, jaw, and face; 2) rigidity, or stiffness of the limbs and trunk; 3) bradykinesia, or slowness of movement; and 4) postural instability, or impaired balance and coordination.
  • tremor or trembling in hands, arms, legs, jaw, and face
  • rigidity or stiffness of the limbs and trunk
  • bradykinesia or slowness of movement
  • postural instability or impaired balance and coordination.
  • PD usually affects people over the age of 50. Early symptoms are subtle and occur gradually. In some people the disease progresses more quickly than in others. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. As the disease progresses, the shaking, or tremor, which affects the majority of PD patients may begin to interfere with daily activities.
  • PD sleep disorders
  • Other symptoms of PD may include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions.
  • PD is diagnosed based on clinical criteria; currently no blood or laboratory tests have been proven to help in diagnosing sporadic PD. Diagnoistic criteria have been developed by the National Institute of Neurological Disorders and Stroke (NINDS) . Gelb et al . , 1999, Arch Neurol, 56: 33-39. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases.
  • NINDS National Institute of Neurological Disorders and Stroke
  • Anticholinergics may help control tremor and rigidity.
  • Other drugs such as bromocriptine, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing the neurons to react as they would to dopamine.
  • An antiviral drug, amantadine also appears to reduce symptoms.
  • Other treatments for PD including gene therapy, are currently under investigation.
  • the present invention provides a method for promoting functional regeneration and sprouting of striatal dopaminergic fibers which comprises contacting cells with an agent which increases extracellular glycine level so as to enhance NMDA receptor-dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • This invention also provides a method for treating a disease comprises administering to a subject a compound which increases extracellular glycine level so as to enhance NMDA receptor-dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • This invention further provides a use of glycine uptake inhibitors in the preparation of a medicament for promoting functional regeneration and sprouting of striatal dopaminergic fibers wherein the medicament increases extracellular glycine level so as to enhance NMDA receptor-dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • This invention even further provides a use of glycine uptake inhibitors in the preparation of a medicament for treating a disease wherein the medicament increases extracellular glycine level so as to enhance NMDA receptor-dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • Figure 1A Overlay of axonal growth cone images taken at 0 and 60' time points (left) and following superfusion (right) with glutamate/0Mg 2+ for 3 min (70') and one hour later (130') ⁇
  • the graph below shows the shift to faster growth rates in response to 200uM glutamate/0Mg 2+ as well as to the NMDA receptor agonist tetrazol-glycine (20uM) .
  • Figure IB Images of a growth cone before and following a 3 min AMPA (50uM) stimulus.
  • the graph shows the shift to slower rates in response to AMPA, as well as to glutamate/0Mg 2+ in the presence of AP-5 (50uM) , an NMDA receptor antagonist. (All treatments are significantly different from controls with p ⁇ 0.01, Kolgomorow-Smirnov test, scale bar: 20um) .
  • Figure 2A Distribution of growth rate change in response to glutamate/0Mg 2+ (light green circles) and to glutamate/0Mg 2+ in the presence of the CaMKII inhibitor KN93 (light blue triangles) or its inactive form KN92 (dark green diamonds) .
  • Figure 2B Distribution of growth rate change in response to AMPA (light red circles) and to glutamate/0Mg 2+ in the presence of the NMDA receptor AP-5 (dark red diamonds) , and for both stimuli in the presence of the calcineurin inhibitor cyclosporine A (light blue circles for AMPA, dark blue diamonds for glutamate/0Mg 2+ plus AP-5) . (Green and red traces are significantly different from controls with p ⁇ 0.01, blue traces are not . ) Figure 3.
  • RWI-D-132-1 Promotes Dopaminergic Sprouting In the Dorsal Striatum
  • FIG. 3A Coronal striatal sections immune-stained for the dopamine transporter (DAT) .
  • DAT dopamine transporter
  • FIG. 1 RWI-D-132-1 Treatment Enhances Dopamine Release and Uptake Seven weeks following the 6-OHDA injection living brain slices of untreated and treated mice were prepared for cyclic voltammetry recordings of electrically evoked dopamine release .
  • FIG. 4A Dopamine release was recorded at three sites in control and lesioned hemispheres as indicated. Example of signals evoked by a single electrical pulse are shown for the control and lesioned side (untreated) .
  • the peak amplitude of the signal reflects release and uptake parameters (peak amplitude is higher with more release and less uptake) whereas the falling phase (half-life) mostly reflects uptake kinetics (wider with less uptake) .
  • Figure 5B A scatter plot of data of untreated and treated mice at 3 and 7 weeks. For all mice there was improvement, i.e. less lateralization, between the 3- and 7-week time points. There was a clear difference between untreated (open triangles) and treated (filled circles) mice. The average improvement in lateralization between 3 and 7 weeks was 18.5% in controlled mice, and 33.8% in treated mice.
  • This invention provides for a method for promoting functional regeneration and sprouting of striatal dopaminergic fibers which comprises contacting cells with an agent which increases extracellular glycine level so as to enhance NMDA receptor- dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • the cells are substantia nigra neurons.
  • the agent is a glycine uptake inhibitor.
  • the glycine uptake inhibitor is (R)-(N[3- ( 4 ' -fluorophenyl ) -3- ( 4 ' -phenylphenoxy) propyl] ) sarcosine.
  • the glycine uptake inhibitor is 4-Phenyl piperdine sulfonyl.
  • This invention also provides for a method for treating a disease comprises administering to a subject a compound which increases extracellular glycine level so as to enhance NMDA receptor-dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • the disease is Parkinson's disease.
  • the compound comprises a glycine uptake inhibitor and a carrier.
  • the compound comprises a therapeutically effective amount of the glycine uptake inhibitor and a pharmaceutically acceptable carrier.
  • the glycine uptake inhibitor is (R)-(N[3- ( 4 ' -fluorophenyl ) -3- ( 4 ' -phenylphenoxy) propyl] ) sarcosine. In one embodiment, the glycine uptake inhibitor is 4-Phenyl piperdine sulfonyl.
  • the compound comprises lOmg of the glycine uptake inhibitor per kg of the body weight of the subject. In one embodiment, the compound is administered every other day .
  • the glycine uptake inhibitor increases glycine level in prefrontal cortex of the subject by at least 40% at 60-90 minutes after administration.
  • This invention further provides a use of glycine uptake inhibitors in the preparation of a medicament for promoting functional regeneration and sprouting of striatal dopaminergic fibers wherein the medicament increases extracellular glycine level so as to enhance NMDA receptor-dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • This invention even further provides a use of glycine uptake inhibitors in the preparation of a medicament for treating a disease wherein the medicament increases extracellular glycine level so as to enhance NMDA receptor-dependent transmission, thereby promoting functional regeneration and sprouting of striatal dopaminergic fibers.
  • Ventral midbrain cultures are prepared from TH-GFP mice, cultured for 5-9 days, incubated with the ratiometric calcium- indicator fura-2 for 30 minutes, and transferred into imaging chambers. Cultures are stimulated for 3 minutes with either glutamate in Mg 2+ -free Tyrodes's (glutamate/0Mg 2+ ) or with AMPA with or without prior depletion of the Ca 2+ stores using caffeine, the SERCA inhibitor thapsigargin, or ryanodine. Calcium signals are acquired at 0.5 Hz for 2 minutes prior, 3 minutes during, and 5 minutes following the stimulus. The results of this experiment reveal the origin of the calcium signals observed in response to NMDA and AMPA receptor activation that determine whether axonal growth is accelerated or inhibited.
  • Example 2 Effects of Dopaminergic Cells' NMDA Receptors on Developmental Innervation of the Striatum In Vivo
  • NR1 receptor flox/flox mice from Dr. Susumu Tonegawa, which we crossed with DAT-Cre mice to obtain animals that lack the NMDA receptor only in dopaminergic cells.
  • mice with the desired genotype NRlf/f DAT-Cre +/-. Striatal sections from brains of adult mice are immunostained for TH and assessed stereoligically for changes in the dopaminergic innervations density .
  • NMDA receptor activation stimulates axonal growth in dopaminergic neurons.
  • NMDA agonists can cause neurotoxicity and so a different approach has been pursued to enhance NMDA signaling in vivo, which is to raise the extracellular level of glycine, a co- agonist of the NMDA receptor, by blocking glycine uptake transporters (Lechner, 2006, Curr Opin Pharmacol , 6, 75; Lindsley et al . , 2006, Curr Top Med Chem, 6, 1883).
  • the glycine transporter-1 (GlyT-1) inhibitor, (R) - (N [ 3- (4 ' - fluorophenyl ) -3- ( 4 ' -phenylphenoxy) propyl ] ) sarcosine (NFPS) has been tested in small-scale trials, and has been found to improve positive, negative, cognitive and general psychiatric symptoms in schizophrenic patients with no significant side effects (Tsai et al . , 2004, Biol Psychiatry, 55, 452; Lane et al., 2005, Arch Gen Psychiatry, 62, 1196; Lane et al., 2008, Biol Psychiatry, 63, 9) .
  • NFPS neuropeptide-binding protein
  • glycine uptake inhibitors include, but are not limited to, those compounds disclosed in U.S. Patent Application Publication No. 2007/0105902, PCT International Publication No. WO/2005/014563, and PCT International Publication No.
  • the control group receives i.p. injections of saline, the treatment groups receive i.p. injections of NFPS (lOmg/kg) every other day starting at the peak of axonal loss in the striatum until the time at which about 50% of recovery is achieved (about 4 weeks in rats) .
  • Glycine uptake inhibitors have been developed to date for treatment of schizophrenia, as there is evidence that inhibition of NMDA may be involved in the negative symptoms of that disease. Many companies have developed or are developing different classes of glycine uptake inhibitors intended as treatments for schizophrenia. However, to our knowledge none are testing these drugs for treatment of PD. The rationale for using glycine uptake inhibitors for treatment of Parkinson's disease comes from our recent work in the area.
  • sprouting needs to be directed to the right target, as undirected sprouting may cause adverse effects and not restore normal function.
  • synaptic connections are shaped by activity and neurotransmitter release (Spitzer, 2006, Nature, 444, 707).
  • Dopaminergic axon terminals express glutamate receptors and their major striatal target is the glutamatergic cortico-striatal synapse (Gracy, 1996, Brain Res, 739, 169) .
  • NMDA receptor activity has an influence on dopaminergic projection in vivo by using a dopamine neuron- specific NR1 receptor KO mouse, and test whether NMDA receptor activity influences the regeneration of dopaminergic fibers.
  • a way of enhancing NMDA receptor activity in vivo without causing neurotoxicity is to increase extracellular levels of glycine (an NMDA receptor co-agonist) via inhibitors of glycine uptake, an approach that has already been used in animal models and in small-scale trials on schizophrenia in humans.
  • glycine transporter-1 (GlyT-1) inhibitor (R) - (N[3- ( 4 ' -fluorophenyl ) -3- ( 4 ' -phenylphenoxy) propyl ] ) sarcosine (NFPS) promotes functional regeneration and sprouting of striatal dopaminergic fibers. Therefore, glycine uptake inhibitors would be beneficial in therapeutic treatment of Parkinson's disease patients.
  • An important new goal related to the location of the glycine transport inhibitor effect is to identify from where the glutamate input that affects dopamine axon growth originates.
  • An obvious source is cortico- and thalamo-striatal terminals, but the glutamate could also be released as an auto-feedback signal from dopaminergic axons themselves.
  • Dopamine neurons express the vesicular glutamate transporter 2 (Vglut2) during development and following 6-OHDA lesions (Dal Bo et al . , 2008, Neuroscience, 156 ( 1 ) : 59-70 ; Berube-Carriere et al., 2009, J Comp Neurol., 517 ( 6) : 873- 91 ) .
  • Vglut2 vesicular glutamate transporter 2
  • the role of Vglut2 in dopamine neurons is not well understood.
  • Glutamate transmission by dopamine neurons may play a role in the reward pathway in the N. accumben (Chuhma et al . , 2004, J Neurosci., 24 (4) : 972-81; Birgner et al .
  • Example 5 Effects of Glycine Uptake Inhibitors In Genetically Based Mouse Models of Parkinson' s Disease
  • glycine uptake inhibitors are restricted to the 6-OHDA model, or whether axonal sprouting is also promoted in genetically based mouse models of Parkinson's disease.
  • Mice that overexpress LRRK2 containing the R1441G mutation have been reported to show age- dependent deficits in motor behavior, dopamine release, and dopamine neurite degeneration (Li et al . , 2009, Nat Neurosci., 12 (7) : 826-8) .
  • mice While effects on the morphology may not be detectable in these mice, the functional read out, i.e. motor behavior and evoked dopamine release and uptake, can be straightforwardly determined.
  • These transgenic mice may provide a useful model to show glycine uptake inhibitors promote functional compensatory sprouting of dopamine neurites while a subset of neurons develops neurite degeneration.
  • Example 6 Enhancing NMDA Receptor-Dependent Transmission via Glycine Uptake Inhibitor To Promote Regeneration of Dopaminergic Fibers In 6-OHDA Mouse Model Of Parkinson' s Disease
  • mice were treated with compound RWI-D-132-1, provided by Dr. Craig Lindsley at Vanderbilt University (Wolkenberg et al . , 2009, Bioorg Med Chem Lett. 19(5) : 1492) .
  • RWI-D-132-1 was injected (30mg/kg) i.p. 3 times a week for 4 weeks, beginning 3 weeks after the lesion .
  • coronal striatal brain slices were prepared from control and treated mice at 7 weeks. Dopamine release was evoked by bipolar electrical stimulation at 3 different sites: directly under the corpus callosum, in the middle of the dorsal striatum and in the ventral part of the dorsal striatum in control and lesioned hemispheres.
  • mice receive unilateral intrastriatal 6-OHDA injections. Three weeks after the lesion the dorsal striatum was devoid of dopamine neurites. After an additional four weeks, a gradual and partial dopaminergic reinnervation of the dorsal striatum occurred in untreated mice.
  • Our data on evoked dopamine release and motor-behavior recovery further support a beneficial effect of glycine uptake inhibitors on dopamine release and uptake and paw usage.
  • glycine uptake inhibitors a class of drugs that is already being considered for treatment of symptoms in schizophrenia patients, promote functional dopaminergic sprouting and could reverse the dopaminergic fiber loss seen in Parkinson's disease patients.
  • Example 7 Glycine Uptake Inhibitor Treatment Enhances Behavioral Improvement In Mice
  • mice treated with glycine transporter-1 inhibitor in a behavioral test, the so called “corridor test", which is very sensitive to lesion size (Dowd et al . , 2005, Brain Research Bulletin, 68:24-30).
  • the test indicates lateralized sensory-motor neglect.
  • a hungry mouse is placed in a narrow corridor containing pairs of containers with sugar pellets placed adjacently along the left and right wall.
  • Unilaterally lesioned mice tend to collect sugar pellets only from the ipsilateral side.
  • FIG. 5B shows a scatter plot of the data of untreated and treated mice at 3 and 7 weeks. For all mice there was improvement, i.e. less lateralization, between the 3 and 7 week time points. There was a clear difference between untreated (open triangles) and treated (filled circles) mice. The average improvement in lateralization between 3 and 7 weeks was 18.5 % in control mice, and 33.8 % in treated mice.

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Abstract

La présente invention concerne une nouvelle approche dans la thérapie de la maladie de Parkinson : au lieu de se concentrer sur la survie des cellules, notre approche se concentre sur l'amélioration de la réinnervation des zones du cerveau appauvries en dopamine par rapport aux zones adjacentes survivant à la maladie. Il s'est avéré que les inhibiteurs du recaptage de la glycine améliorent la transmission dépendant du récepteur NMDA et favorisent la réinnervation dopaminergique de l'aire striée en modifiant son activité et la transmission synaptique tout en réduisant la neurotoxicité dans un modèle souris de maladie de Parkinson basé sur les toxines. L'invention concerne en outre des procédés destinés à favoriser la régénération fonctionnelle et le bourgeonnement des fibres dopaminergiques de l'aire striée. L'invention concerne également un procédé de traitement d'une maladie comprenant l'administration à un sujet d'un composé favorisant la régénération fonctionnelle et le bourgeonnement des fibres dopaminergiques de l'aire striée.
PCT/US2011/059989 2010-11-10 2011-11-09 Utilisation d'inhibiteurs du recaptage de la glycine dans la thérapie de la maladie de parkinson Ceased WO2012064854A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070105902A1 (en) * 2003-11-12 2007-05-10 Lindsley Craig W 4-Phenyl piperdine sulfonyl glycine transporter inhibitors
US20100048653A1 (en) * 2005-07-14 2010-02-25 The University Of British Columbia Neuroprotective modulation of nmda receptor subtype activities

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070105902A1 (en) * 2003-11-12 2007-05-10 Lindsley Craig W 4-Phenyl piperdine sulfonyl glycine transporter inhibitors
US20100048653A1 (en) * 2005-07-14 2010-02-25 The University Of British Columbia Neuroprotective modulation of nmda receptor subtype activities

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SCHMITZ ET AL.: "Glutamate controls growth rate and branching of dopaminergic axons.", J. NEUROSCI., vol. 29, no. 38, 2009, pages 11973 - 11981 *

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WO2012064854A1 (fr) Utilisation d'inhibiteurs du recaptage de la glycine dans la thérapie de la maladie de parkinson

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