WO2010015037A1 - Procédés et compositions thérapeutiques - Google Patents

Procédés et compositions thérapeutiques Download PDF

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Publication number
WO2010015037A1
WO2010015037A1 PCT/AU2009/001012 AU2009001012W WO2010015037A1 WO 2010015037 A1 WO2010015037 A1 WO 2010015037A1 AU 2009001012 W AU2009001012 W AU 2009001012W WO 2010015037 A1 WO2010015037 A1 WO 2010015037A1
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dopamine
agonist
agent
cells
snc
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PCT/AU2009/001012
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English (en)
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Timothy Douglas Aumann
Malcolm Horne
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Howard Florey Institute
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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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention is generally directed to the field of neurological therapy. More particularly, the present invention contemplates therapeutic protocols for neurological conditions associated with abnormal levels of dopamine including pharmaceutical compositions for use in such therapeutic protocols.
  • Dopamine is a hormone and neurotransmitter occurring in a wide variety of animals, including both vertebrates and invertebrates. In the brain, dopamine functions as a neurotransmitter, activating the five types of dopamine receptor, Dl, D2, D3, D4 and D5, and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra and hypothalamus.
  • Dopamine is associated with many neurological activities, including having important roles in behavior and cognition, motor activity, motivation and reward, regulation of milk production, sleep, mood, attention and learning.
  • Dopaminergic neurons i.e., neurons whose primary neurotransmitter is dopamine
  • VTA ventral tegmental area
  • substantia nigra pars compacta arcuate nucleus of the hypothalamus, olfactory bulb and retina. Accordingly, abnormal levels of dopamine (i.e. either too much or too little) has a major impact on the health of an individual.
  • dopamine deficiency is associated with such symptoms as resting tremor, rigidity, bradykinesia (slowing of physical movement), postural instability, physical fatigue, overt fatigue and lethargy, negative behavioral feelings, concentration deficit, weight gain, addictive behavior, reduced libido and/or impotence, depression, alcoholism and attention deficit and hyperactivity disorder (ADHD).
  • ADHD attention deficit and hyperactivity disorder
  • Parkinson's disease also known as “Parkinson disease” or “PD”
  • Parkinson's disease is a chronic and progressive degenerative disorder of the central nervous system that impairs movement, speech and other functions.
  • Non-motor symptoms include pain/discomfort, anxiety, depression, slowness of thinking, memory deficits, tiredness, disturbed sleep, constipation, bladder problems, sexual difficulties, speech and swallowing difficulties.
  • the primary motor symptoms are the result of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain, particularly those in the substantia nigra.
  • PD is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise and nutrition. At present, there is no cure for PD, but medications or surgery can provide some relief from the motor symptoms, at least in the short- to medium-terms (5-10 years on average). Neurological disease and disorders contribute immense distress to families and potential injuries to patients, and represent a major cost burden to the community and the healthcare system.
  • the present invention relates generally to neurological therapy, and in particular the treatment or prevention of neurological conditions which include neurological diseases and disorders as well as neurodegenerative conditions associated with abnormal levels of dopamine.
  • abnormal dopamine levels it is meant a deficiency or elevation in the level of dopamine. This is generally determined relative to a subject regarded as healthy i.e. with no symptoms of a neurological disorder. It may also be determined by a standardized control based in the measurement of a range of subjects over time. In cases where there is a deficiency in the level of dopamine, the present invention contemplates promoting recruitment of new dopaminergic cells.
  • nneurological diseases and conditions associated with a dopamine deficiency contemplated for treatment herein include Parkinson's Disease (PD), dystonia, Tourettes syndrome, restless legs, certain psychoses, attention deficit and hyperactivity disorder (ADHD), cognition disorders, motor control disorders, abnormal lactation, sleep disorders, memory deficit, attention deficit, problem solving deficit, learning deficit, abnormal moods, social disorders, abnormal libido, anhedonia and eating disorders.
  • PD Parkinson's Disease
  • ADHD attention deficit and hyperactivity disorder
  • cognition disorders motor control disorders
  • abnormal lactation sleep disorders
  • sleep disorders memory deficit
  • attention deficit problem solving deficit
  • learning deficit abnormal moods
  • social disorders abnormal libido, anhedonia and eating disorders.
  • the present invention provides for decreasing the number of dopaminergic cells.
  • Such neurological diseases and conditions associated with enhanced levels of dopamine include schizophrenia, drug addiction, obsessive compulsive disorder, mania and certain psychoses.
  • the present invention is directed, in one aspect, to a method for treating or preventing a neurological disease or disorder associated with decreased dopamine levels in a subject, the method comprising administering to the subject an agent which modulates neuronal cell excitability, thereby increasing dopaminergic cells.
  • an agent which modulates neuronal excitability in the manufacture of a medicament for treating a neurological condition, and in particular, a neurological condition associated with dopamine deficiency.
  • “Modulates” refers to targeting different cell surface molecules to either decrease or increase neuronal excitability thereby altering the number of dopaminergic cells.
  • the present invention also contemplates a method of preventing or treating a neurological condition associated with enhanced levels of dopamine, the method comprising administering to a subject an agent which modulates neuronal cell excitability, thereby decreasing the number of dopaminergic cells. Also contemplated is the use of an agent which modulates neuronal excitability in the manufacture of a medicament for treating a neurological condition, and in particular, a neurological condition associated with enhanced levels of dopamine.
  • the subject is one in need of therapy.
  • the treatment of subjects considered “at risk” of developing symptoms of a neurological condition as well as the treatment of asymptomatic subjects are encompassed by the present invention.
  • Therapeutic protocols contemplated herein may also be provided in conjunction with behavioral modification protocols.
  • the neuronal cell to be the subject of excitation modulation is from the substantia nigra pars compacta (SNc).
  • the present invention is further directed to a method for treating a subject with abnormal levels of dopamine, the method comprising administering to the subject an agent which modulates excitability of a cell and in particular neurons in the SNc.
  • Agents which modulate the excitability of a neuron contemplated for use herein include agonists and antagonists specific for: calcium-activated potassium (Kc a ) channels (including K Ca 2.1, Kc a 2.2, Kc a 2.3, K Ca 3.1, also referred to as SK channels), voltage- activated calcium (Cay) channels (including Cayl.l, Cay 1.2, Cayl.3, Cay 1.4, Ca ⁇ 2.1, Ca ⁇ 2.2, Ca ⁇ 2.3, Cav3.1, Ca ⁇ 3.2, Ca ⁇ 3.3), ATP-sensitive potassium (KA TP ) channels, G protein-coupled inwardly rectifying potassium (GIRK) channels, glutamate receptors (including AMPA, NMDA and GIuRs), GABA receptors (including GABA A and GABA B ) and acetylcholine (ACh) receptors (including nicotinic and muscarinic).
  • Kc a calcium-activated potassium
  • Cay voltage- activated calcium
  • agents which specifically target small-conductance calcium- activated potassium (Kc a ) channels (including Kc a 2.1, Kc a 2.2, Kc a 2.3, Kc a 3.1), also referred to as "SK channels" are contemplated for use in the methods and compositions of the present invention.
  • a method for treating a disease or disorder associated with a dopamine deficiency comprising administering to a subject an SK channel agonist.
  • the SK channel agonists are selected from NS309, zoxazolamine, chlorzoxazone, and a benzimidazolone or benzothiazole such as EBIO or a derivative thereof as defined by Formula I.
  • a method of increasing dopaminergic cells in a site deficient in dopamine producing cells comprising administering a SK specific agonist to a subject.
  • a method for decreasing the number of dopaminergic cells comprising administering to a subject an SK channel antagonist.
  • SK channel antagonists include, tamapin, apamin, UCL 1848, leiurotoxin, UCL 1684, PO5, Leu-Dab7, Tsk, dequalinium, NS8593, UCL 1407, atracurium, tubocurarine, pancuronium, N-methyl-laudanosine, trifluperazine, bicuculline methiodide, gallamine, chlorpromazine, carbamazepine, cyproheptadiene, imipramine, tacrine, armitryptyline, 4- AP, decamethonium, hexamethonium and TEA.
  • a method for decreasing the number of dopaminergic cells in a subject comprising administering to a subject an antagonist or agonist of GABAA receptors or an agonist or antagonist of L-type voltage-activated calcium channels.
  • GABAA receptor agonists examples include gaboxadol, isoguvacine, isonipecotic acid, muscimol, CL-218,872 (highly ⁇ l-selective agonist), bretazenil (subtype-selective partial agonist), QH-ii-066 (full agonist highly selective for ⁇ 5 subtype) , THIP, GABA, and ⁇ - alanine.
  • GABAA receptor antagonists examples include bicuculline, gabazine, SR-95531, SR- 95103, TPMPA, picrotoxin and pentylenetetrazol.
  • L-type voltage-activated calcium channel agonists examples include BayK8644, elocalcitol, FPL-64176 and Dehydrodidemnin B.
  • L-type voltage-activated calcium channel antagonists examples include isradipine, dihydropyridines, phenylalkylamines,benzothiazapines and calcicludines.
  • the present invention further relates to the use of the above-mentioned agents in the manufacture of a medicament in a therapeutic protocol for the treatment or prophylaxis of a neurological condition.
  • the present invention extends to therapeutic protocols combining the administration of an agent which modulates the excitability of a neuron with the administration of, for example, levodopa, carbidopa, benserazide, co-careldopa, sinemet, parcopa, co-beneldopa, madopar, duodopa, tolcapone, entacapone, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride, selegiline and/or rasagiline and/or functional derivatives thereof.
  • Combination therapy involving an agent which modulates the excitability of a neuron with behavioural modification protocols to assist in controlling the condition being treated in the subject is also contemplated herein.
  • compositions comprising agents which modulate the excitability of a neuron also form part of the present invention.
  • Figure 1 is a graphical representation showing changes in number of tyrosine hydroxylase immunopositive (TH+, black bars) and immunonegative (TH-, white bars) SNc cells 5 following infusions of "intrinsic" ion-channel agonists or antagonists directly into SNc.
  • ⁇ SE D Mean ( ⁇ SE) change in number of SNc cells (left SNc minus right SNc) in mice receiving the different treatments.
  • the number of total cells (TH+ & TH-, gray) is not statistically significantly (p>0.01 z-test) altered in the infused (left) SNc relative to the control (right) SNc in every treatment group except for the pooled nimodipine-treated group (L-typej).
  • Figure 2 is graphical representation showing Changes in number of tyrosine hydroxylase immunopositive (TH+, black bars) and immunonegative (TH-, white bars) SNc cells following infusions of "extrinsic" ion-channel (GABAA) agonists or antagonists directly into SNc or following disruption of afferent feedback pathways to SNc cells originating from the striatum (Quinolinic Acid or QA lesions).
  • GABAA "extrinsic" ion-channel
  • ⁇ SE Mean ( ⁇ SE) change in number of SNc cells in mice receiving the different treatments.
  • TH- (white) cells are significant for the GABAA agonist and antagonist only.
  • the changes in number of total cells is significant in every treatment group except for vehicle and GABAAt (GABAAt is significant at the p ⁇ 0.05 level).
  • Figure 3 is a graphical representation showing a 1-EBIO infusion into SNc for 2 weeks almost completely restores the normal number of tyrosine hydroxylase-positive (dopaminergic) neurons following their degeneration in a 6-OHDA mouse model of Parkinson's disease. 6-OHDA was injected into the left SNc of 8-week old male mice. Two weeks later, once ⁇ 50% of SNc dopaminergic neurons had degenerated, vehicle, lOOuM 1-EBIO or 20OuM 1-EBIO was infused into the same left SNc for a further 2 weeks via a micro-osmotic pump.
  • Figure 4 is a graphical representation showing a systemically administered riluzole for 2 weeks has no beneficial effect on the number of tyrosine hydroxylase-positive
  • 6-OHDA was injected into the left SNc of 8-week old male mice.
  • mice Two weeks later, once -50% of SNc dopaminergic neurons had degenerated, vehicle, 3uM riluzole or 3OuM riluzole was administered to the mice in their drinking water for a further 2 weeks. At the end of the drug administration period vehicle infused mice exhibited an average -50% reduction in the normal number of SNc dopaminergic neurons on the left side. Neither 3uM nor 3OuM riluzole had a significant effect compared with vehicle.
  • a neurological condition includes a single neurological condition, as well as two or more conditions
  • reference to “an agent” includes a single agent, as well as two or more agents
  • reference to “the invention” includes single or multiple aspects of an invention.
  • the present invention is directed to the treatment or prophylaxis of neurological conditions. More particularly, the present invention contemplates the treatment or prevention of a neurological condition associated with abnormal levels of dopamine.
  • the present invention is predicated, in part, on the determination that modulating the excitability of a neuron through different cell surface molecules results in an increase or decrease in the number of dopaminergic cells.
  • Reference to a "condition" includes a disease or a disorder as well as a neurodegenerative condition.
  • the present invention contemplates the administration of agents which modulate neuronal cell excitability to increase the number of dopaminergic cells.
  • the present invention provides the administration of agents which modulate neuronal cell excitability to decrease the number of dopaminergic cells.
  • a method for treating or preventing a neurological disease or disorder associate with dopamine deficiency in a subject, the method comprising administering to a subject an agent which modulates neuronal cell excitability, thereby increasing the number of dopaminergic cells.
  • a method of treating or preventing a neurological condition associated with elevated levels of dopamine in a subject comprising administering to the subject an agent which modulates neuronal cell excitability thereby decreasing the number of dopaminergic cells.
  • an agent which modulates neuronal excitability in the manufacture of a medicament for treating a neurological condition, and in particular a neurological condition associated with abnormal levels of dopamine.
  • the subject being treated may be in need of such treatment or may be "at risk" of developing a neurological condition.
  • the subject may have symptoms or may be asymptomatic of a neurological condition.
  • the subject may also be provided with behavioral modification protocols.
  • Examples of neurological diseases and disorders associated with dopamine deficiency contemplated herein include, Parkinson's Disease (PD), dystonia, Tourettes syndrome, restless legs, psychosis, attention deficit and hyperactivity disorder (ADHD), cognition disorders, motor control disorders, abnormal lactation, sleep disorders, memory deficit, attention deficit, problem solving deficit, learning deficit, abnormal moods, social disorders, abnormal libido, anhedonia and eating disorders.
  • PD Parkinson's Disease
  • ADHD attention deficit and hyperactivity disorder
  • cognition disorders motor control disorders
  • abnormal lactation sleep disorders
  • sleep disorders memory deficit
  • attention deficit problem solving deficit
  • learning deficit abnormal moods
  • social disorders abnormal libido, anhedonia and eating disorders.
  • Examples of neurological diseases and conditions associated with enhanced levels of dopamine contemplated for treatment herein include schizophrenia, drug addiction, obsessive compulsive disorder, mania and psychosis.
  • agents should be understood as a reference to any proteinaceous or non- proteinaceous molecule derived from natural, recombinant or synthetic sources. Useful sources for agents may be identified by a variety of techniques including inter alia, the screening of natural molecular libraries, chemical molecule libraries, phage display libraries and in vitro based libraries. The agents may also be nucleic acid molecules. Furthermore, the agents may be immunoglobulins such as antibodies or fragments or synthetic or modified forms thereof. An "immunoglobulin” includes an immunoglobulin new antigen receptor (IgNAR) from cartilaginous fish such as sharks (see WO2005/118629).
  • IgNAR immunoglobulin new antigen receptor
  • agent may be used interchangeably herein to refer to any agent that induces a desired pharmacological and/or physiological effect. Such effects include decreasing or increasing neuronal excitability and/or altering the number of dopaminergic cells.
  • the terms also encompass pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including, but not limited to, salts, esters, amides, prodrugs, active metabolites, analogs, and the like.
  • agent agents, compounds, active agent, “pharmacologically active agent”, “medicament”, “active”, and “drug”
  • active agent pharmaceutically active agent
  • immediatecament agents that are used
  • drug drug
  • this includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, ester, amides, prodrugs, metabolites, analogs, etc.
  • agents which decrease neuronal excitability include agents which act upon channels and receptors expressed on neuronal cells to directly decrease the level of excitability of the neuron. Conversely, the agent may act indirectly to decrease the level of excitability of the neuron by initiating a cascade of cellular events, the downstream effects of which result in decreased neuronal excitability.
  • Kc a calcium-activated potassium channels (including Kc a 2.1, Kc a 2.2,
  • Kc a 2.3, Kc a 3.1), voltage-activated calcium (Cav) channels including Ca ⁇ l.1, Ca ⁇ l.2,
  • KATP ATP-sensitive potassium
  • GIRK G protein-coupled inwardly rectifying potassium
  • glutamate receptors including AMPA, NMDA and GIuRs
  • GABA receptors including GABAA and GABAB
  • ACh acetylcholine
  • a method for treating a disease or disorder associated with a dopamine deficiency in a subject comprising administering to the subject an SK channel agonist.
  • the agent is one which agonises calcium-activated potassium (Kc 8 ) channels including K Ca 2.1 (also known as SKl, SKCaI or KCNNl), K Ca 2.2 (also known as SK2, SKCa2 or KCNN2), K Ca 2.3 (also known as SK3, SKCa3 or KCNN3) and K Ca 3.1 (also known as SK4, IKl, IKCaI or Gardos channel).
  • Such agents include, without being limited to EBIO, DCEBIO 5 NS309, zoxazolamine, Cyclohexyl-[2-(3,5-dimethyl-pyrazol-l- yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) and their pharmaceutically acceptable salts thereof.
  • SK specific agonist is defined as one which, at one or more doses, has proportionally more activity through SK channels affecting cell excitability than on any other known or unknown ion-channel or receptor affecting cell excitability.
  • Activity in certain aspects means it recruits more SNc dopaminergic cells when administered to normal mice or a mouse model of Parkinson's disease than riluzole. For example 1-EBIO is a more
  • an SK agonist has:
  • At least 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of the its activity is blocked by the administration of a specific SK channel antagonist such as apamin.
  • the specificity of agents for SK channel activity can be measured by placing an electrode inside a cell in which a number of different ion-channels and receptors, including SK channels, are functionally expressed, e.g. SNc dopaminergic cells. Currents passing into and out of the cell through each individual ion-channel or receptor can then be isolated using either controlled voltage steps or exposure to ligands known to specifically activate or inhibit each individual ion-channel or receptor. An agent to be tested would then be applied to the cell and the change in current passing through each individual ion-channel or receptor measured. For example, to measure SK specific current the membrane potential can be stepped from -7OmV +3OmV for 100 ms, then stepped to -9OmV for 1 second.
  • the current thus measured largely comprises current passing through SK channels.
  • SK channel current can be further isolated by applying the SK channel specific antagonist apamin and repeating the above voltage step protocol.
  • the current blocked by apamin will be equal to the current passing through SK channels in the absence of apamin.
  • SK channel agonists include, without being limited to, NS309, zoxazolamine, chlorzoxazone, and a benzimidazolone or benzothiazole such as EBIO or a derivative thereof as defined by Formula I.
  • the present invention provides a method for increasing dopaminergic cells in a site deficient in dopaminergic cells, the method comprising administering a SK specific agonist.
  • the administration of the SK channel specific agonists results in migration or recruitment of dopaminergic cells, such as neurons, to the site of the brain deficient in dopamine. This is in contrast to known treatments of dopamine deficient diseases or disorders where either dopamine per se is administered, or the therapeutic treatment is administered as a neuroprotective.
  • one aspect of the present invention is directed to a method of inducing migration of dopaminergic cells to a site deficient in dopamine producing cells comprising administering a SK specific agonist.
  • a related aspect is directed to a method of recruiting dopaminergic cells to an area deficient in dopamine producing cells comprising administering to a subject a SK specific agonist.
  • the present invention provides for a method of stimulating synthesis of dopamine in resident non-dopaminergic cells, such as neurons, comprising the administration of the SK specific agonists.
  • the SK specific agonist is a Kc a 2.3 specific agonist.
  • the agent is EBIO or a pharmaceutically acceptable salt or derivative thereof.
  • the agent is a benzimidazolone compound defined by Formula (I):
  • R and R 2 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted phenyl, optionally substituted -(CH ⁇ xphenyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted acyloxy, optionally substituted phenoxy and optionally substituted -O(CH 2 ) x phenyl; each R 3 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl alkoxyalkyl, alkoxy, alkoxyalkoxy, cycloalkoxy, halo, haloalkyl, haloalkoxy, hydroxy, thio,
  • alkyl or "alk”, used either alone or in compound words denotes straight chain, or branched alkyl, in certain embodiments Ci -2 O alkyl, e.g. C MO or Ci -6 .
  • straight chain and branched alkyl include methyl, ethyl, ⁇ -propyl, isopropyl, «-butyl, sec-butyl, /-butyl, n-pentyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4- methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,- trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhex
  • alkyl group is referred to generally as "propyl", butyl” etc, it will be understood that this can refer to any of straight or branched isomers where appropriate.
  • An alkyl group may be optionally substituted by one or more optional substituents as herein defined.
  • cycloalkyl includes any of mono or bicyclic, including fused, saturated hydrocarbon resides. Particular examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and and decalinyl.
  • a cycloalkyl group may be optionally substituted by one or more optional substituents as herein defined.
  • alkenyl denotes groups formed from straight chain or branched hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or poly-unsaturated alkyl groups as previously defined, in one aspect C 2-20 alkenyl (e.g. C 2- I 0 or C 2-6 ).
  • alkenyl examples include vinyl, allyl, 1- methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, l-4,pentadienyl, 1,3-hexadienyl and 1,4-hexadienyl.
  • An alkenyl group may be optionally substituted by one or more optional substituents as herein defined.
  • alkynyl denotes groups formed from straight chain or branched hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly- unsaturated alkyl groups as previously defined. Unless the number of carbon atoms is specified the term can refers to C 2-20 alkynyl (e.g. C 2- io or C 2-6 ). Examples include ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be optionally substituted by one or more optional substituents as herein defined.
  • a term written as "[groupA]groupB" is intended to refer to a groupA when linked by a divalent form of groupB, for example, "hydroxyalkyl” is a hydroxy group when linked by an alkylene group, such as HO-CH 2 -.
  • halogen denotes fluorine, chlorine, bromine or iodine (fluoro, chloro, bromo or iodo).
  • acyl either alone or in compound words denotes a group C(O)-R, wherein R is hydrogen (formyl) or an alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, or a -(CH 2 ) x phenyl (where x is 1 -6) residue.
  • R is hydrogen (formyl) or an alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, or a -(CH 2 ) x phenyl (where x is 1 -6) residue.
  • acyl include formyl, straight chain or branched alkanoyl (e.g.
  • Ci -20 such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; benzoyl, phenylacetyl, phenylpropanoyl, phenylbutano
  • Carboxy ester is used here in its broadest sense as understood in the art and includes groups having the formula -CO 2 R, wherein R may be selected from groups including alkyl, alkenyl, alkynyl, cycloalkyl, phenyl and (CH 2 ) x phenyl, where x is 1-6.
  • carboxy ester examples include -C0 2 C] -2 oalkyl, such as CO 2 Ci -6 alkyl, -
  • R residue may be optionally substituted as described herein.
  • sulfonyl either alone or in a compound word, refers to a group S(O) 2 -R 3 wherein R is selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, acyl, and benzyl.
  • R is selected from hydrogen, Ci. 2 oalkyl, phenyl and benzyl.
  • sulfonamide or “sulfonamyl” of "sulfonamido", either alone or in a compound word, refers to a group S(O) 2 NRR wherein each R is independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, acyl, and benzyl.
  • R examples include hydrogen, Ci -2 oalkyl, phenyl and benzyl.
  • at least one R is hydrogen.
  • both R are hydrogen.
  • sulfonate refers to a group SO 3 R wherein each R is independently selected from hydrogen (sulfonic acid), alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, acyl, and benzyl Some examples of R include hydrogen, Ci- 2 oalkyl, phenyl and benzyl.
  • thio is intended to include groups of the formula "-SR" wherein R can be hydrogen (thiol), alkyl, cycloalkyl, alkenyl, alkynyl, phenyl, acyl, and benzyl. Examples of R include hydrogen, C 1-2 oalkyl, phenyl and benzyl.
  • amino includes groups of the formula -NR A R B wherein R ⁇ and R B may be any group independently selected from hydrogen, hydroxyl, alkyl, alkoxyalkyl, alkoxyalkoxy, alkenyl, alkynyl, phenyl, benzyl, cycloalkyl, and acyl, each of which may be optionally substituted.
  • R A and R B together with the nitrogen to which they are attached, may also form a monocyclic, or polycyclic ring system e.g. a 3-10 membered ring, particularly, 5-6 and 9-10 membered systems.
  • Examples of "amino” include -NH 2 , -NHalkyl (e.g. -NHCi- 20 alkyl), -NHalkoxyalkyl, -NHphenyl), -NHbenzyl, -NHacyl (e.g. -NHC(O)C i -20 alkyl, -
  • NHC(O)phenyl NHC(O)phenyl
  • -Ndialkyl wherein each alkyl, for example C 1-20 , may be the same or different, eg NMe 2 , NEt 2 , NPr 2 and N'Pr 2 ).
  • Reference to groups written as "[group] amino" is intended to reflect the nature of the R A and R B groups.
  • alkylamino refers to -NR A R B where one of R A or R B is alkyl and the other is hydrogen.
  • n Dialkylamino refers to -NR A R B where R A and R B are each (independently) an alkyl group.
  • x is 2, 3, 4, 5 or 6.
  • R 3 groups contemplated herein include: Ci -6 alkyl (such as methyl, ethyl, propyl, butyl), C 2-6 alkenyl, C 2-6 alkynl, C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyCi -6 alkyl, (such as hydroxymethyl, hydroxyethyl, hydroxypropyl), Ci -6 alkoxyCi -6 alkyl (such as methoxymethyl, methoxy ethyl, methoxypropyl, ethoxymethyl, ethoxy ethyl, ethoxypropyl), (such as methoxy, ethoxy, propoxy, butoxy), C].
  • 6 alkocyCj. 6 alkoxy (such as methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, propoxymethoxy, propoxyethoxy, propoxypropoxy) C 3 -C 6 cycloalkoxy (cycloprop ' oxy, cyclobutoxy, cyclopentoxyl, cyclohexyloxy), F, Cl, Br, I, haloCi -6 alkyl (such as chloromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl), haloC 1-6 alkoxy, hydroxy, thio (-SH), -SO 2 C ]-6 alkyl, -SO 2 phenyl, -SO 3 H, -SO 3 C ]-6 alkyl, - SO 2 NH 2 , phenyl, benzyl, phenoxy, benzy
  • 6 alkyl (such as methylamino, ethylamino, propylamino ), -NH(C i -6 alky I) 2 (such as dimethylamino, diethylamino, dipropylamino), -NHC(O)C i -6 alkyl (such as -NHC(O)CH 3 ), -N(C(O)C i -6 alkyl) 2 (such as - N(C(O)CH 3 ) 2 ), -NHphenyl, nitro (NO 2 ), cyano (CN) 5 formyl, -C(O)-alkyl (e.g.
  • -C(O)Ci- 6 alkyl 5 such as acetyl
  • O-C(O)-alkyl e.g. -OC(O)C i -6 alkyl, such as acetyloxy
  • benzoyl benzoyloxy, CO 2 H 5 CO 2 Ci -6 alkyl (such as methyl ester, ethyl ester, propyl ester, butyl ester), C0 2 phenyl, C0 2 benzyl, CONH 2 , C(O)NHphenyl, C(O)NHbenzyl 5 C(O)NHC 1- 6 alkyl (such as methyl amide, ethyl amide, propyl amide, butyl amide) C(O)N(C i- 6 alky I) 2 ), H 2 NCi -6 alkyl-, Ci -6 alkylHN-Ci.
  • n is 0 or 1. In another embodiments, n is 2, 3 or 4.
  • optionally substituted means that a group may be unsubstituted or substituted with one or more, same or different, substituents.
  • Optional substitutents contemplated herein include: Ci ⁇ alkyl (such as methyl, ethyl, propyl (n- and /-), butyl(n-, sec- and t-)), C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyCi -6 alkyl, (such as hydroxymethyl, hydroxyethyl, hydroxypropyl), C 1-6 alkoxyCi.
  • 6 alkyl such as -NHC(O)CH 3 ), -N(C(O)Ci. 6 alkyl) 2 (such as -N(C(O)CH 3 ) 2 ), -NHphenyl, nitro (NO 2 ), cyano (CN), formyl, -C(O)- alkyl (e.g. -C(O)C 1-6 alkyl, such as acetyl), O-C(O)-alkyl (e.g.
  • -OC(O)C i- 6 alkyl such as acetyloxy
  • benzoyl benzoyloxy
  • CO 2 H 3 CO 2 Ci -6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester
  • 6 alkyl-, C 1-6 alkyl(O)CC 1-6 alkyl-, O 2 NCi -6 alkyl-, or and 2 adjacent R 3 groups together form C 3 -C 4 alkylene, 0-CH 2 -O or O-(CH 2 ) 2 -O, (and wherein phenyl or benzyl, alone or as part of a group, may be further substituted one or more times by one or more Ci -6 alkyl, halo, hydroxy, hydroxyCi, 6 alkyl, Ci -6 alkoxy, Ci -6 alkoxyCi. 6 alkyl, Ci.
  • optional substituents are selected from: Ci_ 6 alkyl, halo, hydroxy, hydroxyC 1-6 alkyl, Ci ⁇ alkoxy, Ci. 6 alkoxyC] -6 alkyl, Ci- 6 alkoxyCi -6 alkoxy, haloCi. 6 alkyl, haloCi -6 alkoxy, cyano, nitro, OC(O)Ci -6 alkyl, -NH 2 , -NHCi -6 alkyl, -NHC(O)C J -6 alkyl and -N(Ci -6 alkyl)C 1-6 alkyl.
  • Exemplary compounds of Formula (I) include EIBO (l-ethyl-2-benzimidazolone), DCEIBO (5, 6-dichloro- l-ethyl-2-benzimidazolone), l-benzhydryl-2-benzimidazolone,
  • certain compounds of formula (I) may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form, such as enantiomers and diastereomers.
  • the invention thus also relates to optically active compounds and compounds in substantially pure isomeric form at one or more asymmetric centres, e.g., enantiomers having greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, enzymes, or mixtures may be resolved by conventional methods, e.g., chromatography, recrystallization, or use of a resolving agent.
  • the present invention also relates to prodrugs of formula (I). Any compound that is a prodrug of a compound of formula (I) is within the scope and spirit of the invention.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo, either enzymatically or hydrolytically, to the compounds of the invention.
  • Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free thiol or hydroxy group is converted into an ester, such as phosphonate, sulphonate and carboxy esters, such as an acetate, or thioester or where a free amino group is converted into an amide such as a carboxy, phosphonate or sulphonate amide.
  • Procedures for acylating the compounds of the invention for example to prepare ester and amide prodrugs, are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.
  • Esters of carboxylic acid (carboxy) groups are also contemplated.
  • esters C 1-6 alkyl esters; Cj- 6 alkoxymethyl esters, for example methoxymethyl or ethoxymethyl; Ci -6 alkanoyloxymethyl esters, for example, pivaloyloxymethyl; phthalidyl esters; C 3 - 8 cycloalkoxycarbonylCi -6 alkyl esters, for example, 1- cyclohexylcarbonyloxy ethyl; l,3-dioxolen-2-onylmethyl esters, for example, 5-methyl-l,3- dioxolen-2-onylmethyl; and Q-ealkoxycarbonyloxyethyl esters, for example, 1- methoxycarbonyloxy ethyl.
  • Prodrugs of amino functional groups include amides (see, for example, Kyncl et al Adv Bio Sci 20:369, 1979), enamines (see, for example, Caldwell et al J Pharm Sci 60:1810, 1971), Schiff bases (see, for example, United States Patent No. 2,923,661 and Smyth et al. Antimicrob Agents Chemother 19:1004, 1981), oxazolidines (see, for example, johansen et al.
  • Suitable pharmaceutically acceptable salts of compounds of formula (I) include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, adipic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, fendizoic, 4-4' -methyl enebis-3-hydroxy-2 -na
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • Basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides or dialkyl sulfates such as dimethyl and diethyl sulfate.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, ie compounds contemplated by the invention, and one or more molecules of a solvent.
  • Suitable solvents are well understood in the art and include for example, of water, ie to form hydrates, and common organic solvents such as alcohols (methanol, ethanol, isopropanol) and acetic acid. Methods of solvation are generally known within the art, for example, recrystallization from an appropriate solvent.
  • protecting group refers to an introduced functionality which temporarily renders a particular functional group inactive under certain conditions.
  • protecting groups and methods for their installation and subsequent removal at an appropriate stage are described in Protective Groups in Organic Chemistry, 3 rd Edition, T.W.Greene and P. G. Wutz, John Wiley and Sons, 1999, the entire contents of which are incorporated herein by reference.
  • exemplary forms of protected groups include: for amino (NH 2 ) - carbamates (such as Cbz, Boc, Fmoc), benzylamines, acetamides (e.g.
  • acetamide, trifluoroacetamide for carbonyl - acetals, ketals, dioxanes, dithianes, and hydrazones; for hydroxy — ethers (e.g. alkyl ethers, alkoxylalkyl ethers, allyl ethers, silyl ethers, benzyl ethers, tetrahydropyranyl ethers), carboxylic acid esters, acetals (e.g. acetonide and benzylidene acetal); for thio (SH) -ethers (e.g. alkyl ethers, benzyl ethers), esters; and for CO 2 H - esters (e.g. alkyl esters, benzyl esters).
  • hydroxy ethers e.g. alkyl ethers, alkoxylalkyl ethers, allyl ethers, silyl ethers, benzyl ether
  • the present invention provides a method for decreasing dopaminergic cells in a site having an elevated level of dopamine, the method comprising administering a SK specific antagonist, thereby decreasing the number of dopaminergic cells.
  • the administration of SK channel specific antagonists results in a loss of dopaminergic cells, such as neurons, in the site of the brain having enhanced levels of dopamine.
  • a method for decreasing the number of dopaminergic cells comprising administering to a subject an SK channel antagonist.
  • SK channel antagonists include, tamapin, apamin, UCL 1848, leiurotoxin, UCL 1684, PO5, Leu-Dab7, Tsk, dequalinium, NS8593, UCL 1407, atracurium, tubocurarine, pancuronium, N-methyl-laudanosine, trifluperazine, bicuculline methiodide, gallamine, chlorpromazine, carbamazepine, cyproheptadiene, imipramine, tacrine, armitryptyline, 4- AP, decamethonium, hexamethonium and TEA.
  • a method for treating a disease or disorder associated with enhanced levels of dopamine comprising administering to a subject a GABAA agonist or antagonist.
  • GABAA agonists contemplated for use in the methods and compositions of the present invention include, without being limited to, gaboxadol, isoguvacine, isonipecotic acid, muscimol, CL-218,872 (highly ⁇ l -selective agonist), bretazenil (subtype-selective partial agonist), QH-ii-066 (full agonist highly selective for ⁇ 5 subtype) , THIP, GABA, and ⁇ - alanine.
  • GABAA antagonists contemplated for use in the methods and compositions of the present invention include, without being limited to, bicuculline, gabazine, SR-95531, SR-95103, TPMPA, picrotoxin and pentylenetetrazol.
  • a method for treating a disease or disorder associated with enhanced levels of dopamine comprising administering to a subject a L- type voltage-activated calcium channel agonist or antagonist.
  • L-type voltage-activated calcium channel agonist contemplated for use in the compositions and methods of the present invention include BayK8644, elocalcitol, FPL-64176 and Dehydrodidemnin B.
  • L-type voltage-activated calcium channel antagonist contemplated for use in the compositions and methods of the present invention include isradipine, dihydropyridines, phenylalkylamines,benzothiaza ⁇ ines and calcicludines.
  • the agent is an antagonist of voltage-activated calcium (Cay) channels including Ca ⁇ l.1 (also known as ⁇ lS or L-type), Ca ⁇ l .2 (also known as ⁇ lC or L-type), Cavl.3 (also known as ⁇ lD or L-type), Ca ⁇ l.4 (also known as ⁇ lF or L-type), Ca ⁇ 2.1 (also known as ⁇ lA or P/Q-type), Ca ⁇ 2.2 (also known as ⁇ lB or N-type), Ca ⁇ 2.3 (also known as ⁇ lE or R-type), Ca ⁇ 3.1 (also known as ⁇ lG or T-type), Ca ⁇ 3.2 (also known as ⁇ lH or T-type), Ca ⁇ 3.3 (also known as all or T-type).
  • Ca ⁇ l.1 also known as ⁇ lS or L-type
  • Ca ⁇ l .2 also known as ⁇ lC or L-type
  • Cavl.3 also known as ⁇ lD or L-type
  • Ca ⁇ l.4 also known as ⁇ lF or
  • Such agents include, without being limited to, amlodipine besylate, cilnidipine, diltiazem hydrochloride, isradipine, loperamide hydrochloride, nifedipine, niguldipine hydrochloride, nimodipine, nitrendipine, SR33805 and verapamil hydrochloride, ⁇ -Conotoxin GVIA, ⁇ -Conotoxin MVIIC, Mibefradill dihydrochloride, NNC 55-0396 dihydrochloride, Ruthenium Red and their pharmaceutically acceptable salts and derivatives thereof.
  • the agent is an agonist of voltage-activated calcium (Cay) channels including Ca ⁇ l.1 (also known as ⁇ lS or L-type), Ca ⁇ l.2 (also known as ⁇ lC or L-type), Cavl .3 (also known as ⁇ lD or L-type), Ca ⁇ l.4 (also known as ⁇ lF or L-type), Ca ⁇ 2.1 (also known as ⁇ lA or P/Q-type), Ca ⁇ 2.2 (also known as ⁇ lB or N-type), Ca ⁇ 2.3 (also known as ⁇ lE or R-type), Ca ⁇ 3.1 (also known as ⁇ lG or T-type), Ca ⁇ 3.2 (also known as ⁇ lH or T-type), Ca ⁇ 3.3 (also known as all or T-type).
  • Such agents include, without being limited to, Bay K8644, dihydropyridine, nifedipine and FPL-64176.
  • the agents used in the methods of the present invention include agonists specific for ATP-sensitive potassium (KATP) channels.
  • KATP ATP-sensitive potassium
  • Such agents include, without being limited to, cromakalim, diazoxide, glimepiride, levcromakalim, minoxidil, nicorandil, P1075, pinacidil, Y-26763, Y-27152 and ZM 226600, and their pharmaceutically acceptable salts or derivatives thereof.
  • the agents of the present invention include antagonists specific for ATP-sensitive potassium (KATP) channels.
  • Such agents include, without being limited to, gyburide, tetraphenylphosphonium, 5-Hydroxydecanoate (5-HD), glibenclamide and imidazolines.
  • the agents of the present invention also include agonists specific for G- protein coupled inwardly rectifying potassium (GIRK) channels.
  • GIRK G- protein coupled inwardly rectifying potassium
  • Such an agents includes, without being limited to, tenidap, and its pharmaceutically acceptable salts or derivatives thereof.
  • the agents of the present invention also include antagonists specific for G-protein coupled inwardly rectifying potassium (GIRK) channels.
  • GIRK G-protein coupled inwardly rectifying potassium
  • agents include, without being limited to, delta-opioid receptor antagonists and tertiapin-Q.
  • the agents of the present invention are antagonists specific for glutamate receptors.
  • glutamate receptors include, without being limited to, AMPA, Kainate, NMDA, Group I metabotropic, Group II metabotropic and Group III metabotropic glutamate receptors.
  • the agents of the present invention are agonists specific for glutamate receptors.
  • Such agents include, without being limited to, 3,5-dihydroxyphenylglycine, eglumegad, Biphenylindanone A, DCG-IV and L-AP4.
  • the agents of the present invention include agonists specific for kainate receptors.
  • Such agents include, without being limited to, ATPA, domoic acid, 5- lodowillardiine, kainic acid and SYM 2081, and their pharmaceutically acceptable salts or derivatives thereof.
  • the agents of the present invention include antagonists specific for kainate receptors. Such agents include, without being limited to, ACET, CNQX, DNQX and Philanthotoxin. In another aspect, the agents of the present invention include antagonists specific for AMPA/kainate receptors. Such agents include, without being limited to, CNQX, DNQX 5 Evans blue, NBQX, SYM 2206, UBP 282 and ZK 200775 and their pharmaceutically acceptable salts or derivatives thereof.
  • the agents of the present invention include agonists specific for AMPA/kainate receptors.
  • Such agents include, without being limited to, CIP-A, Cyclothiazide, ( ⁇ )-AMPA hydrobromide, L-(+)-2-Amino-6 ⁇ phosphonohexanoic acid, ATPA, Domoic acid, Quisqualic acid and Kainic acid.
  • the agents of the present invention encompass antagonists specific for NMDA receptors, such as AP5, AP7, 4-carboxyphenylglycine, CPG 37849, CPG 39551, CGS 19755, chlorpheg, co 101244 hydrochloride, CCP, CPP-ene, LY 235959, PMPA, PPDA, PPPA, Ro 04-5595 hydrochloride, Ro 25-6981 maleate, SDZ 220-040, SDZ 220-581, ACBC, CGP 78608 hydrochloride, 7-Chlorokynurenic acid, CNQX, 5,7- dichlorokynurenic acid, felbamate, gavestinel, HA-996, L-689,560, L-701,252, L-701,324, l-(l,2-diphenylethyl)piperidine 1, IEM 1460, loperamide hydrochloride, memantine hydrochloride, norketamine hydrochloride, remace
  • the agents of the present invention encompass agonists specific for NMDA receptors.
  • Such agents include, without being limited to, L-aspartic acid, ibotenate, glutamate, aspartate, D-serine and N-phthalamoyl-L-glutamic acid.
  • the agent is an antagonist specific for Group I metabotrophic glutamate receptors.
  • agents include, without being limited to, ACDPP hydrochloride, AIDA, AP3, Bay 36-7620, 3-Carboxy-4-hydroxy ⁇ henylglycine, 4-Carboxy-3- hydroxyphenylglycine, 4-Carboxyphenylglycine, CPCCOEt, E4CPG, Fenobam, HexylHBO, JNJ 16259685, LY 367385, 3-MATIDA, MCPG, MPEP hydrochloride, MPMQ hydrochloride, PHCCC 5 SIB 1757, SIB 1893, YM 298198 hydrochloride, Desmethyl-YM 298198, DMeOB and ACPT-II, and their pharmaceutically acceptable salts or derivatives thereof.
  • the agent is an agonist specific for Group I metabotrophic glutamate receptors.
  • agents include, without being limited to, 3,5-dihydroxyphenylglycine, L- glutamate, ibotenic acid and CHPG.
  • the agent is an antagonist specific for Group II metabotrophic glutamate receptors.
  • agents include, without being limited to, APICA, E4CPG, EGLU, LY 341495, MCPG 5 MSPG and MTPG, and their pharmaceutically acceptable salts or derivatives thereof.
  • the agent is an agonist specific for Group II metabotrophic glutamate receptors.
  • agents include, without being limited to, DCG-IV, (S)- and (R)-2-Amino- 4-(4-hydroxy[l,2,5]thiadiazol-3-yl)butyric Acid, L-glutamate, (1S,3S)-1- aminocyclopentane-1, 3-dicarboxylate ((I S, 3 S)-ACPD) and (2S, I 1 R, 2'R, 3'R)-2-(2',3'- dicarboxy cyclopropyl)glycine (DCG-IV) .
  • the agent is an antagonist specific for Group III metabotrophic glutamate receptors.
  • agents include, without being limited to, CPPG, LY 341495, MAP4, MPPG, MSOP, MSPG and UBPl 112, and their pharmaceutically acceptable salts or derivatives thereof.
  • the agent is an agonist specific for Group III metabotrophic glutamate receptors.
  • agents include, without being limited to, L-AP4, L-glutamate and ACPR-I .
  • the agent is an antagonist specific for nicotinic acetylcholine (Ach) receptors, including, DMAB-anabaseine dihydrochloride, Benzoquinonium dibromide, alpha-Bungarotoxin, Chlorisondamine diiodide, Dihydro-beta-erythroidine hydrobromide, Methyllycaconitine citrate, MG 624, Pancuronium dibromide, TMPH hydrochloride and Catestatin, and their pharmaceutically acceptable salts or derivatives thereof.
  • Ach nicotinic acetylcholine
  • the agent is an agonist specific for nicotinic acetylcholine (Ach) receptors.
  • Such agents include, without being limited to, dimethylphenylpiperazinium (DMPP), nicotine, epibatidine, suxamethonium, varenicline and choline.
  • the agent is an antagonist specific for muscarinic acetylcholine (Ach) receptors.
  • Such agents include, without being limited to, AF-DX 116, AF-DX 384, AQ- RA 741, 4-DAMP, DAU 5884 hydrochloride, Dimethindene maleate, Ipratropium bromide, J 104129 fumarate, Nitrocaramiphen hydrochloride, PD 102807, Pirenzepine dihydrochloride, Scopolamine hydrobromide, Telenzepine dihydrochloride, Tropicamide, W-84 dibromide and Zamifenacin fumarate, and their pharmaceutically acceptable salts or derivatives thereof.
  • the agent is an agonist specific for muscarinic acetylcholine (Ach) receptors.
  • Such agents include, without being limited to, acetylcholine, oxotremorine, muscarine, carbachol, McNA343, and methacholine.
  • the amount of agent used is an effective amount meaning it is used in an amount effective to modulate neuronal excitability.
  • the amount of agent administered means an amount necessary to at least partially attain the desired physiological effect or to delay the onset or inhibit progression or halt altogether the onset or progression of a particular dopamine related condition of the subject to be treated, the taxonomic group of the individual to be treated, the degree of protection desired, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
  • the amount of agent includes an amount which ameliorates at least to some extent symptoms of a neurological condition, especially neurological conditions associated with an abnormal level of dopamine such as a dopamine deficiency or elevation in dopamine levels.
  • agents which modulate neuronal excitability include agents which act upon channels and receptors expressed on neuronal cells to directly alter the level of excitability of the neuron. Conversely, the agent may act indirectly to modulate the level of excitability of the neuron by initiating a cascade of cellular events, the downstream effects of which result in a change in neuronal excitability.
  • treating encompass the administration of an agent which modulates neuronal excitability to a subject having a neurological disease or disorder and/or which results in an amelioration or decrease in one or more of the symptoms associated with a neurological condition.
  • the terms “treating” or “treatment” encompass the administration of an agent which modulates neuronal excitability, thereby increasing levels of dopamine, to a subject having a neurological disease or disorder and/or which results in the amelioration or decrease in one or more symptoms associated with a neurological condition associated with decreased levels of dopamine.
  • symptoms may include, for example, resting tremor, rigidity, bradykinesia, postural instability, physical fatigue, overt fatigue and lethargy, negative behavioral feelings, concentration deficit, weight gain, addictive behavior and reduced libido and/or impotence, depression, alcoholism and ADHD.
  • Treatment may also include the regeneration, generation, recruitment or migration of dopaminergic neurons and in particular neurons within the substantia nigra pars compacta (SNc).
  • the terms “treating” or “treatment” encompass the administration of an agent which modulates neuronal excitability, thereby decreasing levels of dopamine, to a subject having a neurological disease or disorder and/or which results in the amelioration or decrease in one or more symptoms associated with a neurological condition associated with elevated levels of dopamine.
  • prevention as used herein may refer to a delay in the onset of physical manifestations of a disease associated with abnormal levels of dopamine. Prevention may also include a decrease or delay in the onset of pathology associated with a syndrome associated with abnormal levels of dopamine, such as depigmentation of the substantia nigra and intracellular inclusion bodies.
  • Dopamine deficiency is defined as a decrease in levels of dopamine compared to controls. Dopamine deficiency may be measured via either direct measurements of dopamine levels in a subject, or by the onset or presence of symptoms associated with a dopamine deficiency.
  • Enhanced levels of dopamine is defined as an increase in levels of dopamine compared to controls. Enhanced levels of dopamine may be measured via either direct measurements of dopamine levels in a subject, or by the onset or presence of symptoms associated with enhanced levels of dopamine.
  • subject refers to an animal, particularly a mammal and more particularly a primate including a lower primate and even more particularly, a human who can benefit from the methods of the present invention.
  • a subject may also be referred to as a patient, individual, target person etc. Genetic testing of embryos in utero may also identify subjects at risk of developing a neurological disease or condition.
  • a subject regardless of whether human, non-human animal or embryo, may be referred to as an individual, subject, animal, patient, host or recipient.
  • the present invention therefore, has both human and veterinary applications.
  • an "animal” specifically includes livestock animals such as cattle, horses, sheep, pigs, camelids, goats and donkeys. With respect to horses, these include horses used in the racing industry as well as those used recreationally or in the livestock industry.
  • the present invention extends to any subject which is already exhibiting symptoms associated with dopamine deficiency, such as, for example, resting tremor, rigidity, bradykinesia, postural instability, physical fatigue, overt fatigue and lethargy, negative behavioral feelings, concentration deficit, weight gain, addictive behavior and reduced libido and/or impotence, depression, alcoholism and ADHD.
  • the subject may have a family history, genetic trait or predisposition to the development of a dopamine deficient disease or disorder, and accordingly, may be administered doses of an agent which decreases neuronal cell excitability so as to maintain normal or pre- symptomatic levels of dopamine, or dopaminergic cells, including cells in the SNc.
  • the present invention also extends to any subject which is already exhibiting symptoms associated with enhanced levels of dopamine.
  • laboratory test animals include mice, rats, rabbits, guinea pigs and hamsters. Rabbits and rodent animals, such as rats and mice, provide a convenient test system or animal model, as do primates and lower primates.
  • disease disease
  • disorder disorder
  • abnormality may be used interchangeably to refer to a condition characterized by an abnormal level of dopamine produced by the subject.
  • a decrease or reduction in neuronal excitability refers to increased polarization of a neuron's membrane potential and/or decreased rate of action potential discharge by a neuron and can be measured using several techniques which would be known by one of skill in the art. Such techniques include, without being limited to, inserting the tip of an electrode inside a cell or using a voltage sensitive dye to measure the electrical potential difference between the inside and outside of the cell (i.e. potential across the membrane), placing the tip of an electrode outside but near to a cell to measure its rate of action potential discharge.
  • An increase in neuronal excitability refers to decreased polarization of a neuron's membrane potential and/or increased rate of action potential discharge by a neuron and can be measured using several techniques which would be known by one of skill in the art.
  • Such techniques include, without being limited to, inserting the tip of an electrode inside a cell or using a voltage sensitive dye to measure the electrical potential difference between the inside and outside of the cell (i.e. potential across the membrane), placing the tip of an electrode outside but near to a cell to measure its rate of action potential discharge.
  • neuroneuronal cell refers to a cell of the nervous system which is electrically excitable.
  • the neuron is selected from dopaminergic cells, or precursors thereof.
  • Dopaminergic cells are cells that can synthesize the neurotransmitter dopamine.
  • Dopaminergic precursor cells are cells that have the potential to synthesize the neurotransmitter dopamine.
  • Dopamine precursor cells express dopaminergic developmental markers including, but not limited to, Lmxlb, Pitx-3, Engrailed 1 & 2 and/or Nurr-1.
  • Dopaminergic precursor cells may also be mature cells expressing neurotransmitters other than dopamine that can be induced to express dopamine. Such cells include, but are not limited to, catecholamine (adrenaline, noradrenaline) producing cells and GABA producing cells.
  • the neurons or dopaminergic neurons are in the SNc.
  • the present invention is further directed to a method for increasing dopamine production in a neuron by modulating the excitability of the neuron.
  • the dopamine production may be increased in any part of the brain.
  • dopamine production is increased in dopaminergic neurons.
  • the dopaminergic neurons are within the SNc, Hippocampus, Cerebral cortex, Ventral tegmental nucleus (AlO), Retrorubral field (A8), Retina, Hypothalamus, Olfactory bulb, Preoptic areas, Tuberohypophyseal, Incertohypothalamic, and Medullary periventricular area.
  • the present invention extends to a method for facilitating dopamine production in a subject or within particular neurons in a subject, the method comprising administering to the subject an effective amount of an agent which modulates neuronal excitability.
  • Particular neurons include neurons within the SNc.
  • the present invention further contemplates a method for ameliorating the symptoms of dopamine deficiency in a subject, the method comprising administering to the subject an effective amount of an agent which modulates neuronal excitability.
  • Also contemplated by the present invention is a method for treating a dopamine deficient disease or disorder comprising administering an agent which modulates neuronal excitability in conjunction with one or more of levodopa, carbidopa, benserazide, co- careldopa, sinemet, parcopa, co-beneldopa, madopar, duodopa, tolcapone, entacapone, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, lisuride, selegiline and rasagiline.
  • Combination therapy may also be in conjunction with behavioural modification protocols for subjects suffering from diseases or disorders, especially those which have a dopamine deficiency component.
  • the present invention is further directed to a method for decreasing dopamine production by modulating the excitability of the neuron.
  • the dopamine production may be decreased in any part of the brain.
  • dopamine production is decreased in dopaminergic neurons.
  • the dopaminergic neurons are within the SNc, Hippocampus, Cerebral cortex, Ventral tegmental nucleus (AlO),
  • Retrorubral field (A8) Retina, Hypothalamus, Olfactory bulb, Preoptic areas, Tuberohypophyseal, Incertohypothalamic, and Medullary periventricular area
  • the present invention extends to a method for reducing dopamine production in a subject or within particular neurons in a subject, the method comprising administering to the subject an effective amount of an agent which modulates neuronal excitability.
  • Particular neurons include neurons within the SNc.
  • the present invention further contemplates a method for ameliorating the symptoms of enhanced levels of dopamine in a subject, the method comprising administering to the subject an effective amount of an agent which modulates neuronal excitability.
  • a method for treating a disease or disorder associated with enhanced levels of dopamine comprising administering an agent which modulates neuronal excitability in conjunction with one or more of known drugs which are used to treat diseases or disorders associated with enhanced levels of dopamine.
  • Combination therapy may also be in conjunction with behavioural modification protocols for subjects suffering from diseases or disorders, especially those which have an enhanced level of dopamine.
  • in-conj unction is meant simultaneous administration in the same formulation or in two different formulations via the same or different routes or sequential administration by the same or different routes.
  • conjunction also includes the use of two or more agents in the same therapeutic protocol.
  • sequential administration is meant a time difference of from seconds, minutes, hours or days between the administration of the two types of molecules. These molecules may be administered in any order.
  • administering refers to the delivery of an agent to a desired area of the subject.
  • the agents of the present invention are administered directly to the area of the brain where the neurons in a normal subject produce normal levels of dopamine. These levels would be sufficient to maintain dopamine at levels which prevent the onset of signs or symptoms of disease which are indicative of the development of abnormal levels of dopamine.
  • signs or symptoms include, without being limited to, Bradykinesia, loss of postural reflexes, tremor, rigidity, autonomic failure, sleep disturbance, disturbed impulse control.
  • pre-clinical signs or pathology may be prevented or diminished.
  • Such pre-clinial signs include Lewy bodies in susceptible neurons from regions including the SNc, the gut, locus ceruleus and cerebral cortex in addition to loss or death of neurons in these areas.
  • control subject may be a subject to which an agent described herein is not administered or to whom a placebo is administered or a subject which produces abnormally low levels of dopamine which are associated with one or more of the typical symptoms of dopamine deficiency or enhanced levels of dopamine.
  • Delivery of the agents may be via any mechanism which allows the agent to cross the blood brain barrier (BBB) 5 so as to deliver the agent to those cells or areas in the brain in which dopamine production would treat or prevent the onset of a dopamine deficient disease or disorder.
  • BBB blood brain barrier
  • Agents may also be conjugated to targeting moieties to target particular areas of the brain or particular cells within the brain.
  • Such delivery methods include, without being limited to, disruption of the BBB, either by osmotic means or biochemically by the use of vasoactive substances such as bradykinin.
  • disruption of the BBB either by osmotic means or biochemically by the use of vasoactive substances such as bradykinin.
  • vasoactive substances such as bradykinin.
  • systemic delivery of an SK agonist together with bradykinin or a bradykinin B 2 agonist are examples of an SK agonist together with bradykinin or a bradykinin B 2 agonist.
  • Also contemplated as a means for delivering the agents of the present invention across the BBB is the use of endogenous transport systems, including carrier mediated transporters such as glucose and amino acid carriers; receptor-mediated transcytosis; active efflux transporters and retrograde transport.
  • carrier mediated transporters such as glucose and amino acid carriers
  • receptor-mediated transcytosis such as glucose and amino acid carriers
  • active efflux transporters such as retrograde transport.
  • lipophilic and hydrophobic molecules of low molecular weight which cross the BBB can also be used to transport the agents of the present invention to the brain.
  • the neural connections between the nasal mucosa and the brain provide a unique pathway for noninvasive delivery of therapeutic agents to the central nervous system, including the brain.
  • the olfactory neural pathway provides both intraneuronal and extraneuronal pathways into the brain.
  • the intraneuronal pathway involves axonal transport and requires hours to days for drugs to reach different brain regions.
  • the extraneuronal pathway relies on bulk flow transport through perineural channels which deliver drug directly to the brain parenchymal tissue or to the cerebrospinal fluid (CSF) 5 or to both. This extraneuronal pathway allows therapeutic agents to reach the brain within minutes. Intranasal delivery of agents to the CSF is, therefore, contemplated.
  • Invasive delivery strategies include, for example, mechanical procedures, such as implantation of an intraventricular catheter, followed by pharmaceutical infusion into the ventricular compartment.
  • Another invasive strategy for delivering therapeutic compounds to the central nervous system is by intracartoid infusion of highly concentrated osmotically active substances, such as mannitol or arabinose. Their high local concentration causes shrinkage of capillary endothelial cells in the vasculature of the brain, resulting in a transient opening of the tight junctions which enable molecules to traverse the BBB.
  • Another pharmacological method for delivering the subject agents across the BBB is to covalently couple the agent to a peptide for which a specific receptor-mediated transcytosis system exists.
  • an agent of the present invention to insulin to be transported across the BBB by insulin receptor-mediated transcytosis.
  • insulin insulin receptor-mediated transcytosis.
  • the agent Upon entry into the brain interstitial space, the agent is then released from the transport vector (insulin) to interact with its own receptor.
  • Other methods include, for example, coupling the agent to a monoclonal antibody specific for a marker present on the surface of a target cell population.
  • the agent could be coupled to a monoclonal antibody to the transferrin receptor.
  • Also contemplated by the present invention are methods of treating a disease or disorder associated with a dopamine deficiency by modifying the neuronal cells, either in vivo or ex vivo, to increase the expression of one or more of SK channels, KATP channels, GIRK channels, GABA receptors, or decrease the level of expression of voltage-activated calcium channels, glutamate receptors, nicotinic ACh receptors and/or muscarinic ACh receptors.
  • a disease or disorder associated with enhanced levels of dopamine by modifying the neuronal cells, either in vzvo or ex vivo, to decrease the expression of one or more of SK channels, KATP channels, GIRK channels, GABA receptors, or increase the level of expression of voltage-activated calcium channels, glutamate receptors, nicotinic ACh receptors and/or muscarinic ACh receptors.
  • nucleic acid molecule specific for one of the channels or receptors defined herein may be ligated to an expression vector capable of expression in a prokaryotic cell (e.g. E.colf) or a eukaryotic cell (e.g. yeast cells, fungal cells, ⁇ nsect cells, mammalian cells or plant cells).
  • the nucleic acid molecules may be ligated or fused or otherwise associated with a nucleic acid molecule encoding another entity such as, for example, a nucleic acid molecule which is specific for a neuronal marker.
  • nucleic acid molecule may also be part of a vector such as an expression vector.
  • Methods suitable for decreasing the expression of a gene associated with, for example, a particular channel or receptor include the use of sense and anti-sense molecules, single- stranded and double-stranded RNA molecules, RNAi, neutralizing antibodies, or the like. Also contemplated by the present invention is the use of an agent which modulates neuronal excitability in the manufacture of a medicament for the treatment of a neurological disease or disorder associated with abnormal levels of dopamine.
  • agent which modulates neuronal excitability in the manufacture of a medicament for the treatment of a disease or disorder associated with a dopamine deficiency.
  • agents include, for example, SK channel agonists.
  • the present invention is directed to the use of an agent which modulates neuronal excitability in the manufacture of a medicament for treating Parkinson's Disease.
  • agents include, for example, SK channel agonists.
  • an agent which modulates neuronal excitability in the manufacture of a medicament for the treatment of a neurological disease or disorder associated with enhanced levels of dopamine.
  • agents include, for example, SK channel antagonists, GABAA receptor agonists and antagonists and L-type calcium activated agonists or antagonists,
  • the present invention is directed to the use of an agent which modulates neuronal excitability in the manufacture of a medicament for treating Schizophrenia.
  • agents include, for example, SK channel antagonists, GABAA receptor agonists and antagonists and L-type calcium activated agonists or antagonists.
  • mice All animals used for experiments were age-matched (8 week old), male, C57BL6J mice. All mice were housed in standard mouse boxes. They were kept in a constant 12 hour light-dark cycle (light 7am to 7pm). Standard laboratory mouse chow and water were available to mice ad libitum.
  • Animal models of Parkinson's disease involve administering one of a number of different neurotoxins that selectively injure or kill dopamine neurons in the substantia nigra pars compacta (SNc) of the brain.
  • animals of choice include mice, rats and monkeys.
  • Neurotoxins include 6-hydroxy-dopamine (6-OHDA), l-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) and the insecticide/piscicide/pesticide rotenone. These neurotoxins are delivered systemically or by direct injection into the brain.
  • Dopamine neurons are grown in a dish in the laboratory from cells that have been isolated from the brain or other regions of the body. These dopamine cell cultures can also be exposed to the above neurotoxins to cause death or injury to dopaminergic cells.
  • Drugs were infused directly into the substantia nigra pars compacta (SNc) on the left side of the brain using a micro-osmotic pump attached to a brain infusion kit (an example is ALZET [reg trade mark] Model 1002), e.g. Figure IA.
  • the brain infusion kit comprised a length (2-3 cm) of -lmm inner diameter polyethylene tubing attached to a stainless steel cannula, the tip of which was implanted in the SNc (see Surgery section below), e.g. Figure IB.
  • the pump system delivered the drug solution constantly at a rate of ⁇ 0.25 ⁇ l per hour for 14 days.
  • the micro-osmotic pump and attached brain infusion kit were pref ⁇ lled with drug solution (Table 1) one day before surgery and incubated overnight in sterile physiological saline solution at 37 0 C to ensure they were delivering the drug at the time of implantation.
  • Mice were anaesthetized with 0.1 ml/1 Og body weight chloral hydrate (5% w/v in sterile PBS) and placed in a stereotaxic headframe. The skin overlying the SNc was incised and retracted and a 2mm diameter hole was drilled in the skull at stereotaxic coordinates Bregma -3mm, lateral 1.5mm (left side of the brain).
  • the cannula was inserted vertically into the brain through this hole to a depth of 4mm below the brain's surface and glued to the skull with dental cement.
  • the osmotic pump attached to the cannula was inserted into a subcutaneous pocket created in the mid-scapular regions of the animal's back.
  • the skin was then sutured over the pump, cannula and connecting polyethylene tubing.
  • the animal was removed from the frame, given analgesic (Meloxicam, 3 mg/kg s.c.) and placed under a heat-lamp until it recovered from the anaesthetic.
  • mice were given an overdose of anesthetic (Lethabarb) and intracardially perfused with heparinized phosphate buffered saline (PBS) at 37°c followed by 4% v/v paraformaldehyde (1.15ml x body weight in grams). Brains were removed and placed in 30% v/v sucrose in PBS for 2-3 days. Frozen coronal sections (16 ⁇ m) were cut serially through the SNc on both sides of the brain with a cryostat, mounted on gelatinized microscope slides and stored at -80°C.
  • anesthetic (Lethabarb) and intracardially perfused with heparinized phosphate buffered saline (PBS) at 37°c followed by 4% v/v paraformaldehyde (1.15ml x body weight in grams).
  • Brains were removed and placed in 30% v/v sucrose in PBS for 2-3 days. Frozen coronal sections (16 ⁇ m) were cut serially through
  • TH tyrosine hydroxylase
  • the SNc was identified by the spatial distribution of TH-positive cells together with clear anatomical landmarks/boundaries which separate TH-positive cells in SNc from those in surrounding nuclei (i.e. ventral tegmental area (VTA) and retrorubral field (A8)).
  • TH- positive and TH-negative neurons within SNc were identified by the presence and absence of TH immunoreactivity, respectively ( Figure 1C). Only neurons were counted, glial cells were excluded on the basis of soma size. Cell numbers were estimated using an unbiased stereological method.
  • a grid program Step 1 a grid program
  • Membrane potential changes in SNc DAergic neurons are driven by membrane conductances (ion-channels or receptors) that can be broadly categorized as either "intrinsic” or “extrinsic". Intrinsic conductances drive membrane potential in the absence of influence from other cells. For example, the spontaneous pacemaker oscillations ( ⁇ 3- 5Hz) in the membrane potential of SNc DAergic neurons persist even after all extrinsic cellular influences have been removed. This pacemaker activity is mostly driven by interplay between Ca 2+ entry through voltage-activated Ca 2+ channels (T-, L-, and P/Q- type, and small-conductance, Ca 2+ -activated potassium (SK) channels.
  • T-, L-, and P/Q- type small-conductance, Ca 2+ -activated potassium (SK) channels.
  • Each depolarizing phase usually evokes a single Na action potential resulting in the characteristic tonic discharge of these neurons.
  • extrinsic conductances are driven by stimuli extrinsic to the cell, most notably synaptic conductances, which, on SNc DAergic neurons, are mostly inhibitory or GABAergic (60-80%) rather than excitatory or glutamatergic.
  • SK channel agonists (1-EBIO or riluzole) resulted in more TH+ and less TH-
  • L-type voltage-activated Ca 2+ channel drugs were infused directly into SNc for 2 weeks.
  • Infusion of the L-type Ca 2+ channel agonist FPL64176 (10OnM, Tocris) resulted in a similar effect to SK channel inhibition.
  • the number of TH+ SNc cells decreased by -14% (-750 cells less than the -5500 TH+ cells present in vehicle-infused mice) and the number of TH- SNc cells increased by an equal amount (Figure ID), i.e. an apparent decrease in TH expression to below detectable levels in ⁇ 750 cells.
  • L-type Ca 2+ channel antagonist nimodipine L-type Ca 2+ channel antagonist nimodipine (lO ⁇ M, Tocris) had a similar although much larger effect on the number of TH+ cells, reducing them by -2300 or -40%, there was not an equal but opposite increase in the number of TH- cells. Instead, L-type Ca 2+ channel blockade reduced the number of TH- cells by -450 ( Figure ID). In other words, L-type Ca 2+ channel blockade for 2 weeks depleted both TH+ and TH- SNc cells.
  • SNc neuronal excitability was altered independent of any specific ion-channel or receptor by infusing 3OmM K into SNc for 2 weeks.
  • the effect was similar to SK channel inhibition and L-type Ca 2+ channel facilitation, namely a decrease in number of TH+ cells (-350) and an increase in number of TH- cells (-350), with no change in total (TH+ & TH-) cell number (Figure ID).
  • neuronal excitability can regulate the numbers of TH+ and TH- SNc cells, possibly by affecting TH expression in these cells. If this is the case then any ion-channel or receptor affecting SNc cell excitability, including those mediating synaptic input to these cells ("extrinsic" conductances), should also regulate the numbers of TH+ and TH- SNc cells.
  • mice infused with 200 ⁇ M 1-EBIO exhibited only a -20% reduction, on average, in number of dopaminergic cells, which is a statistically significant improvement (figure 3 right column).
  • lOO ⁇ M 1-EBIO made no difference, on average, but a few mice showed marked improvement (figure 3 middle column).
  • the ability of a non-specific SK channel agonist, riluzole, to restore the number of SNc dopaminergic cells using the same experimental protocol was also tested.
  • Riluzole has been contemplated for use as a Parkinson's disease therapeutic, but as a neuroprotective agent (i.e. to prevent death of SNc dopaminergic neurons in the first place) as opposed to a neurorestorative agent, as contemplated here. It also has activity on non-SK ion-channels and receptors affecting the excitability of SNc neurons (e.g. voltage-activated sodium channels and NMDA receptors), and as such may not be as effective as more specific SK channel agonists like 1-EBIO.
  • non-SK ion-channels and receptors affecting the excitability of SNc neurons e.g. voltage-activated sodium channels and NMDA receptors
  • these ion-channels and receptors represent novel therapeutic targets for treating neurological disorders associated with abnormal levels of dopamine.
  • drugs, or their derivatives, that facilitate or inhibit the function of these ion-channels and receptors represent novel therapeutics for treating neurological disorders associated with abnormal levels of dopamine.
  • Dopamine neurons either in vivo or in vitro, are exposed to one of the neurotoxins. After a delay to allow time for dopamine neurons to die, a drug that facilitates SK channel function (e.g. 1 -EBIO) is provided to the cells. Following treatment the cells are assayed for expression of tyrosine hydroxylase (TH, a rate limiting enzyme in dopamine synthesis) using a marker for TH (e.g. immunohistochemical).
  • TH tyrosine hydroxylase
  • a rotation assay is used to assay dopamine expression behaviourally (Glick et al, Biochem Pharmacol 23 (22) :3223 -5, 1974; Kelly PH Brain Res 100(1) ⁇ 63-9, 1975; Reavill et al Biochem Pharmacol 32(5):S65-70, 1983; Olds et al Synapse 59(8):532-44, 2006).
  • An animal is injected systemically with amphetamine, which causes SNc neurons to release dopamine, or apomorphine, which is a dopamine receptor agonist. The animal is then placed on the ground and the number of times it rotates left and right are counted.

Abstract

La présente invention concerne d'une manière générale le domaine de la thérapie neurologique. Plus particulièrement, la présente invention envisage des protocoles thérapeutiques pour des conditions neurologiques associées à une déficience en dopamine, comprenant des compositions pharmaceutiques en vue d'une utilisation dans de tels protocoles thérapeutiques.
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WO2014201411A1 (fr) * 2013-06-13 2014-12-18 Veroscience Llc Compositions et méthodes pour le traitement des troubles métaboliques
WO2017066444A1 (fr) * 2015-10-13 2017-04-20 Children's National Medical Center Traitement de troubles d'apprentissage et d'autres troubles neurologiques avec un/des inhibiteur(s) des canaux sk
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CN105712994A (zh) * 2016-03-30 2016-06-29 中国医学科学院药物研究所 咪唑酮-吗啡喃及其制备方法和应用
CN105712994B (zh) * 2016-03-30 2017-05-10 中国医学科学院药物研究所 咪唑酮‑吗啡喃及其制备方法和应用
CN111867588A (zh) * 2018-03-13 2020-10-30 法国国家科学研究中心 用于治疗病变前庭病症的小电导钙活化的k+通道的调节剂和药物组合物
WO2019175278A1 (fr) * 2018-03-13 2019-09-19 Centre National De La Recherche Scientifique (Cnrs) Modulateurs de canaux k+ activés par le calcium à faible conductance et compositions pharmaceutiques destinées à être utilisées dans le traitement de troubles vestibulaires lésionnels
US20200093806A1 (en) * 2018-09-20 2020-03-26 Ovid Therapeutics Inc. Use of gaboxadol for the treatment of tourette syndrome, tics and stuttering
US10765666B2 (en) * 2018-09-20 2020-09-08 Ovid Therapeutics Inc Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
US11090293B2 (en) 2018-09-20 2021-08-17 Ovid Therapeutics Inc. Use of gaboxadol for the treatment of Tourette syndrome, tics and stuttering
US11690829B2 (en) 2018-12-17 2023-07-04 Ovid Therapeutics Inc. Use of gaboxadol for the treatment of non-24 hour sleep-wake disorder
WO2021052952A1 (fr) * 2019-09-16 2021-03-25 Universite de Bordeaux Méthodes de traitement et/ou de prévention de troubles et de symptômes associés aux canalopathies bkca et/ou sk
US11364228B2 (en) 2019-12-18 2022-06-21 Ovid Therapeutics Inc. Gaboxadol for therapeutic treatment of 1p36 deletion syndrome
US11919911B2 (en) 2020-06-15 2024-03-05 Novartis Ag Methyl (r)-2-(fluoromethyl)-5-oxo-4-phenyl-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate and methyl (r)-2-(fluoromethyl)-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as CAV1.2 activators
US11453679B2 (en) 2020-06-16 2022-09-27 Novartis Ag Methyl 2-methyl-5-oxo-1,4,5,7-tetradhydrofuro[3,4-b]pyridine-3-carboxylate compounds as Cav1.2 activators
WO2023009397A1 (fr) * 2021-07-28 2023-02-02 Florida Atlantic University Board Of Trustees Nouveau traitement médicamenteux de troubles cognitifs associés à la schizophrénie

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