US20050020483A1 - Sigma ligands for neuronal regeneration and functional recovery - Google Patents

Sigma ligands for neuronal regeneration and functional recovery Download PDF

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US20050020483A1
US20050020483A1 US10/868,048 US86804804A US2005020483A1 US 20050020483 A1 US20050020483 A1 US 20050020483A1 US 86804804 A US86804804 A US 86804804A US 2005020483 A1 US2005020483 A1 US 2005020483A1
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ligand
sigma
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pharmaceutical composition
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Donna Oksenberg
Mattias Rickhag
Mehrdad Shamloo
Karoly Nikolich
Roman Urfer
Tadeusz Wieloch
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MS Science Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to methods of treatment to achieve neuronal regeneration in subjects with neurodegenerative disorders.
  • the present invention relates to the use of sigma receptor ligands to facilitate neuronal regeneration and functional recovery in subjects after neurodegenerative disease.
  • the existence of the sigma receptor was proposed by Martin et al. (1976) J. Pharmacol. Exp. Ther. 197: 517-532 to explain the psychotomimetic effects of benzomorphans.
  • the sigma receptor was thought to be a novel opioid receptor.
  • the binding of the benzomorphans to the sigma receptor is not antagonized by naloxone, the classic opioid receptor antagonist.
  • the benzomorphans bind to a site that is distinct from the phencyclidine receptor on the N-methyl-D-aspartate (NMDA) receptor complex.
  • NMDA N-methyl-D-aspartate
  • the sigma receptor consists of two subtypes, named sigma-1 and sigma-2. Hellewell and Bowen (1990) Brain Res., 527: 224-253 were the first to define the characteristics of the two putative sigma receptor subtypes.
  • the primary pharmacological distinction between these two sites is the affinity of the (+) isomers of the benzomorphan opiates for the binding sites.
  • These compounds, such as (+)SKF 10,047 (NANM) and (+)pentazocine show nearly two orders of magnitude higher affinity for the sigma-1 site compared to the sigma-2 site.
  • the ( ⁇ ) isomers of the benzomorphans show little selectivity between these two sites.
  • the subcellular distribution of sigma-1 receptors in brain includes the hippocampus, cortex layer and olfactory bulb.
  • Sigma-1 is a 26 kDa protein, and the gene encoding the receptor has been cloned. Hydropathy analysis suggested that the sigma-1 receptor has two transmembrane segments. Further, the sigma-1 receptors share no homology with any other known mammalian proteins.
  • sigma receptors Both types of the sigma receptors are expressed in the central nervous system as well as in peripheral tissues. Therefore, ligands for the receptor could be used for the treatment and prevention of neurodegenerative diseases. Consequently, brain sigma receptors have been the subject of intense investigation (Sonders et al. (1988) Trends Neurosci., 1: 37-40). In general, sigma receptors exhibit promiscuous binding to a wide variety of ligands such as psychotic drugs, antidepressants and neurosteroids. They have been demonstrated to play important roles in learning and memory in animal models of amnesia as well as in behavioral models of depression. Numerous studies have demonstrated robust neuroprotective properties of sigma receptor ligands in animal models of cerebral ischemia. The mechanism of neuroprotection for some of these sigma ligands has been controversial because both the sigma receptors and the phencyclidine (PCP) binding sites of the NMDA receptor channel complex have been reported to contribute to these effects.
  • PCP phencyclidine
  • Neurodegenerative diseases are characterized by the dysfunction and death of neurons, leading to the loss of functions mediated by the brain, spinal cord and the peripheral nervous system. These disorders have a major impact on society. For example, approximately 4 to 5 million Americans are afflicted with the chronic neurodegenerative disease known as Alzheimer's disease. Other examples of chronic neurodegenerative diseases include diabetic peripheral neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, Huntington's disease and Parkinson's disease. Normal brain aging is also associated with loss of normal neuronal function and may entail the depletion of certain neurons.
  • Stroke is the third ranking cause of death in the United States, and accounts for half of neurology inpatients. Depending on the area of the brain that is damaged, a stroke can cause coma, paralysis, speech problems and dementia. The major causes of cerebral infarction are vascular thrombosis, cerebral embolism, hypotension, hypertensive hemorrhage, and anoxia/hypoxia. However, the adult brain retains capacity for plasticity and functional reorganization throughout the life span, even after stroke or brain ischemia. Neuronal connections are continuously remodeled. The potential capability of the brain to compensate for the damaged part of the brain has relevance for stroke rehabilitation. Neuroimaging in stroke patients suggests some functional reorganization.
  • one aspect of brain plasticity is that in stroke patients, the neuronal connections can be modified by sensory input, experience and learning, and the brain can respond by functional and structural reorganization, upregulation or downregulation of a neural response to an event, and the establishment of new functional and structural connections by collateral sprouting and compensatory synaptogenesis, as well as neurogenesis.
  • sigma receptor ligands have been found to be neuroprotective (i.e. to protect against neuronal cell death and consequential loss of function) in predictive models used for the testing of drugs for neuroprotective activity.
  • the sigma receptor ligand opipramol was found to protect against ischemia in gerbils and was found to modulate the NMDA-type of glutamate receptors.
  • other sigma ligands including BMY-14802, caramiphen and haloperidol, exhibited properties in in vivo models that were consistent with affording protective effects against NMDA-induced toxicity and seizures (M. Pontecorvo et al., (1991) Brain Res.
  • U.S. Pat. No. 5,736,546 discloses certain 1,4-(diphenylalkyl) piperazine derivatives that are ligands for sigma receptors.
  • SA4503 Nakazawa et al., Neurochem. Int., 32 (1998), 337-343 report that SA4503 is a selective sigma-1 agonist and was found to significantly suppress hypoxia/hypoglycemia-induced neurotoxicity in rat primary neuronal cultures. This neuroprotective action led the authors to suggest that sigma-1 receptors may be useful in the treatment of neurodegeneration (see page 342).
  • SA4503 was found to be active against glutamate neurotoxicity in cultured rat retinal neurons.
  • the authors suggest that sigma-1 receptor agonists may be useful against retinal diseases with neuronal cell death due to ischemia, such as central and branch retinal artery occlusion, diabetes mellitus, age-related macular degeneration, hemoglobinopathies and various types of glaucoma.
  • SA4503 is currently undergoing clinical development for the treatment of depression, and has also been noted as having potential use in the treatment of dementia and drug dependence.
  • U.S. Pat. No. 5,665,725 discloses certain piperidine derivatives that are ligands for sigma receptors.
  • the compounds are said to be useful in the treatment of anxiety, psychosis, epilepsy, convulsion, movement disorders, motor disturbances, amnesia, cerebrovascular diseases, senile dementia of the Alzheimer type and Parkinson's disease.
  • One of the compounds, 1′-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl] spiro [isobenzofuran-1(3H),4′-piperidine] is also known as Lu 28-179 or siramesine.
  • sigma ligands may be useful as neuroprotective agents in the treatment of subjects with neurodegenerative diseases.
  • the sigma ligands facilitate functional recovery in subjects suffering from neurodegenerative disease.
  • the sigma ligands are usefuil as neuroregenerative agents in the treatment of neurodegenerative disease following a neuronal insult.
  • the present invention provides methods and compositions for treating neurodegenerative diseases.
  • the sigma receptor ligands of the invention enhance functional recovery and neuronal regeneration. These molecules can be delivered alone or in combination with additional agents, and are used as neuronal regeneration agents for the treatment of neurodegenerative diseases such as those resulting from ischemic strokes or other insults that injure neurons.
  • the subject invention is directed to a method for treating or preventing neurodegenerative disease in a subject in need thereof.
  • the method comprises administering to the subject a pharmaceutically effective amount of a ligand for the sigma receptor.
  • the invention thus provides methods for treating neurodegenerative disease in a mammalian subject in need thereof to facilitate neuronal regeneration leading to functional recovery after a neurodegenerative disease, the method comprising administering a pharmaceutically effective amount of a sigma receptor ligand to the subject.
  • the present invention provides the use of a sigma ligand in the manufacture of a medicament to facilitate neuronal regeneration leading to functional recovery in a mammalian subject after a neurodegenerative disease.
  • the present invention provides a pharmaceutical composition, which comprises a sigma ligand for treating a mammalian subject to facilitate neuronal regeneration leading to functional recovery after a neurodegenerative disease.
  • the neurodegenerative disease can be ischemic stroke, Alzheimer's disease, diabetic peripheral neuropathy, cancer therapy induced neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, Huntington's disease or Parkinson's disease, but is preferably ischemic stroke, traumatic brain injury, or spinal cord injury.
  • the invention provides methods for administering an additional active agent.
  • the ligands of the invention may be administered in a pharmaceutical composition containing a pharmaceutically acceptable excipient.
  • the excipient may be suitable for oral administration.
  • the composition may be in the form of a tablet, a capsule, or a soft-gel capsule.
  • the excipient may be liquid suited to intravenous, intramuscular, or subcutaneous administration.
  • the excipient may be suited to transdermal administration, or buccal administration.
  • the sigma receptor can be a sigma-1 receptor, a sigma-2 receptor, or a recombinant sigma receptor.
  • the ligand may be non-selective or selecive for the sigma-1 or the sigma-2 receptor.
  • the sigma receptor ligand can be, for example, 5-methoxy-4′-(trifluoromethyl)valerophenone O-(2-aminoethyl)oxime (fluvoxamine), N-(N-benzylpiperidin-4-yl)-4-iodobenzaminde (4-IBP), 1-phenylcyclohexane-1-carboxylic acid-2-morpholinoethyl ester (PRE-084), 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (SA 4503), 1′-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl] spiro [isobenzofuran-1(3H), 4′-piperidine] (siramesine or Lu 28-179), (+)-N-(cyclopropylmethyl)-N-[1-ethyl-1, 4-
  • the present invention provides methods and compositions for the rehabilitation of patients with a central nervous system disorder, such as stroke, spinal cord ischemia, spinal cord injury and traumatic brain injury.
  • a central nervous system disorder such as stroke, spinal cord ischemia, spinal cord injury and traumatic brain injury.
  • the invention is based on the discovery that sigma receptor ligands, when administered to patients, within about 48 hours after a stroke, and for a period of one to three months, preferably administered up to one year, or more preferably, administered continuously, allows the patients to recover from the dysfunctional state.
  • These ligands can be delivered alone or in combination with additional agents. They may be administered, for example, daily over the course of the treatment.
  • the subject invention is directed to a method for treating stroke in a subject, which comprises administering to the subject a pharmaceutically effective amount of a ligand for the sigma receptor immediately after a stroke episode and for a period of one to three months.
  • the ligand for the sigma receptor can be, for example, 5-methoxy-4′-(trifluromethyl)valerophenone O-(2-aminoethyloxime)(fluvoxamine), N-(N-benzylpiperidin-4-yl)-4-iodobenzaminde (4-IBP), 1-phenylcyclohexane-1-carboxylic acid-2-morpholinoethyl ester (PRE-084), 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (SA 4503), 1′-[4[1-(4-fluorophenyl)-1H-indol-3-yl]-1-butyl] spiro [isobenzofuran-1(3), 4′-piperidine] (siramesine or Lu 28-179), (+)-N-(cyclopropylmethyl)-N-[1-ethyl-1, 4-diphen
  • the administration of the sigma ligand to the subject commences not less than 24 hours, such as not less than 48 hours, one week, one month or three months, after a neurodegenerative disease, especially after an ischemic stroke, traumatic brain injury or spinal cord injury.
  • the sigma ligand can be administered repeatedly, for example daily, for a period of, for example, one week, two weeks, one month, three months, one year or longer.
  • the treatment can start at least 24 hours, or at least 48 hours, at least one week after an ischemic stroke, traumatic brain injury or spinal cord injury, and continue for one month, three months, six months or one year.
  • the treatment of the subject can be conducted under the direction of a physician.
  • the physician may assess the subject for evidence of neuronal regeneration.
  • the evidence can be evidence of functional recovery or of a structural change in the brain or spinal cord.
  • the physician can measure one or more functional responses of the subject immediately prior to, or on commencement of the treatment, and again after treatment.
  • treatment can be continued until evidence of neuronal regeneration (or functional recovery) has been obtained.
  • the evidence of functional recovery may be, for example, recovery in a motor skill, cognitive skill, speech or sensory perception and function. Particular mention may be made of recovery in a motor skill and recovery in a cognitive skill.
  • Evidence of neuronal regeneration may also be evidence of a structural change in the brain or spinal cord.
  • a packaged kit for a patient to use in the treatment of a neurodegenerative disease to facilitate neuronal regeneration (or functional recovery).
  • the kit includes a pharmaceutical formulation of a ligand for the sigma receptor, a container housing the pharmaceutical formulation during storage and prior to administration, and instructions, e.g., written instructions on a package insert or label, for carrying out drug administration in a manner effective to treat the neurodegenerative disease to facilitate neuronal regeneration (or functional recovery).
  • the pharmaceutical formulation may be any formulation described herein, e.g., an oral dosage form containing a unit dosage of the ligand for the sigma receptor, the unit dosage being a therapeutically effective dosage for treatment of the disease.
  • agonist means a molecule such as a compound, a drug, an enzyme activator or a hormone that enhances the activity of another molecule or the activity of the sigma receptor site.
  • antagonist means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone, that diminishes or prevents the action of another molecule or the activity of the sigma receptor site.
  • stroke broadly refers to the development of neurological deficits associated with impaired blood flow to the brain regardless of cause.
  • Potential causes include, but are not limited to, thrombosis, hemorrhage and embolism. Thrombus, embolus, and systemic hypotension are among the most common causes of cerebral ischemic episodes.
  • Other injuries may be caused by hypertension, hypertensive cerebral vascular disease, rupture of an aneurysm, an angioma, blood dyscrasias, cardiac failure, cardiac arrest, cardiogenic shock, septic shock, head trauma, spinal cord trauma, seizure, bleeding from a tumor, or other blood loss.
  • ischemic episode is meant any circumstance that results in a deficient supply of blood to a tissue.
  • ischemia When the ischemia is associated with a stroke, it can be either global or focal ischemia, as defined below.
  • the term “ischemic stroke” refers more specifically to a type of stroke that is of limited extent and caused due to blockage of blood flow.
  • the term “ischemic stroke” includes cerebral ischemia after cardiac arrest, stroke, and multi-infarct dementia, including those resulting from surgery. Cerebral ischemic episodes result from a deficiency in the blood supply to the brain.
  • the spinal cord which is also a part of the central nervous system, is equally susceptible to ischemia resulting from diminished blood flow.
  • focal ischemia as used herein in reference to the central nervous system, is meant the condition that results from the blockage of a single artery that supplies blood to the brain or spinal cord, resulting in damage to the cells in the territory supplied by that artery.
  • global ischemia as used herein in reference to the central nervous system, is meant the condition that results from a general diminution of blood flow to the entire brain, forebrain, or spinal cord, which causes the death of neurons in selectively vulnerable regions throughout these tissues. The pathology in each of these cases is quite different, as are the clinical correlates. Models of focal ischemia apply to patients with focal cerebral infarction, while models of global ischemia are analogous to cardiac arrest, and other causes of systemic hypotension.
  • neuroprotective agent as used herein is meant a compound effective to reduce neuronal cell death, including the ability to inhibit the spread of neuronal damage from the initial site of injury.
  • microarray refers to an array of distinct polynucleotides or oligonucleotides synthesized or attached or deposited on a substrate, such as paper, nylon or other type of membrane, filter, chip, glass slide, beads, or any other suitable solid support, at a desired density.
  • an “effective amount” or “pharmaceutically effective amount” refer to a nontoxic but sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a ligand for the sigma receptor disclosed herein required to provide a clinically significant decrease in neurodegenerative disease, such as those resulting from ischemic stroke.
  • An appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the terms “treat” or “treatment” are used interchangeably and are meant to indicate a postponement of development of neurodegenerative diseases and/or a reduction in the severity of such symptoms that will or are expected to develop.
  • the terms further include ameliorating existing neurodegenerative symptoms, preventing additional symptoms, and ameliorating or preventing the underlying metabolic causes of symptoms.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i:e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • physiological pH or a “pH in the physiologically acceptable range” is meant a pH in the range of approximately 7.2 to 8.0 inclusive, more typically in the range of approximately 7.2 to 7.6 inclusive.
  • the term “subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or gender.
  • Such salts include:
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
  • the phrase “optionally another drug” means that the patient may or may not be given a drug other than the sigma receptor ligands.
  • “Another drug” as used herein is meant any chemical material or compound suitable for administration to a mammalian, preferably human, which induces a desired local or systemic effect.
  • this includes: anorexics; anti-infectives such as antibiotics and antiviral agents, including many penicillins and cephalosporins; analgesics and analgesic combinations; antiarrhythmics; antiarthritics; antiasthmatic agents; anticholinergics; anticonvulsants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antisense agents; antispasmodics; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol; antihypertensives; central nervous system stimulants; cough and cold preparations, including decongestants; diuretics; gastrointestinal drugs, including H 2 -receptor antagonists; sympathomimetics; hormones such as estradiol and other steroids, including
  • the Sigma Receptor was identified from a microarray analysis of an enriched environment experiment.
  • the invention further provides methods for the identification of compounds that modulate the expression of the sigma receptor for the treatment of central nervous system disorders and for stimulating nerve cell survival and regeneration in subjects with neurodegenerative disorders.
  • the microarray analysis identified genes that are differentially expressed after cortical ischemia and postischemic environmental enrichment brain tissue, relative to their expression in normal, or non-enriched environment are identified and described
  • the invention provides methods of treating a subject exhibiting changes in the above gene expression, wherein the therapeutic intervention results in cell genesis and an enhanced subsequent functional recovery in brain.
  • the inventors have found that sigma receptors expression decrease in the vulnerable regions after middle cerebral artery occlusion (MCAO) in standard conditions and increase after MCAO when the subject is exposed to conditions of enriched environment. An increase has also been detected after MCAO in the resistant regions of the brain.
  • MCAO middle cerebral artery occlusion
  • sigma receptor ligands are administered after the insult, and for a period of time sufficient to facilitate functional recovery.
  • the pharmaceutical intervention leads to faster functional recovery.
  • an array or a micro array can be used to obtain the gene expression of interest.
  • probe oligonucleotides are immobilized on a solid support, and then contacted with a sample containing labeled target oligonucleotides under hybridization conditions to produce a hybridization pattern.
  • the fluorescence or radioactivity such as 33 P utilized for in situ hybridization, measurements are analyzed to determine the level of hybridization of the targets to the probes.
  • the information is useful in determining gene function, gene-splicing, understanding the genetic basis of disease, diagnosing disease, in developing and monitoring the activity of therapeutic agents, detecting the presence or absence of a polymorphism, and the like (Heller, R. et al. (1997) Proc.
  • the probe and target oligonucleotides can be obtained from the RNA or DNA of a biological sample.
  • the oligonucleotides will generally be a DNA that has been reverse-transcribed from RNA derived usually from a naturally occurring source, where the RNA can be total RNA, PolyA+mRNA, amplified RNA and the like.
  • the initial mRNA sample may be derived from a physiological source including a single-celled organism such as yeast, from a eukaryotic source, or a multicellular organism including plants and animals, particularly mammals and organs, tissues, and cells derived from the mammals such as from any bodily fluids (such as blood, urine, saliva, phlegm, gastric juices, etc.), cultured cells, biopsies, or other tissue preparations.
  • a physiological source including a single-celled organism such as yeast, from a eukaryotic source, or a multicellular organism including plants and animals, particularly mammals and organs, tissues, and cells derived from the mammals such as from any bodily fluids (such as blood, urine, saliva, phlegm, gastric juices, etc.), cultured cells, biopsies, or other tissue preparations.
  • Methods of isolating RNA from cells, tissues, organs or whole organisms are known to those of skill in the art and are described in Sambrook, Fritsch & Maniat
  • the hybridization pattern can be used to determine quantitative information about the genetic profile of the nucleic acids in the sample that was contacted with the array to generate the hybridization pattern, as well as the physiological source from which the labeled sample nucleic acid was derived.
  • the data provides information about the physiological source from which the sample nucleic acids were derived, such as the types of genes expressed in the tissue or cell which is the physiological source, as well as the levels of expression of each gene, particularly in quantitative terms.
  • sigma ligands may facilitate neuronal regeneration and functional recovery by mimicking the effects of an enriched or stimulating environment.
  • the sigma receptor ligands can be used in methods and compositions for treating neurodegenerative diseases, and for improving functional recovery from neurodegenerative diseases.
  • ligands for the sigma receptor are known which may find use with the subject methods.
  • Manallack, D. T. et al., Eur. J. Pharmacol., 144: 231-235 (1987) disclose phencyclidine compounds that have affinity for the sigma binding sites, and that the sigma site affinity was shown to be enhanced by large N-alkyl substituents, e.g., benzyl or phenylethyl.
  • Largent, B. L. et al., Mol. Pharmacol., 32: 772-784 (1987) teach that several piperidine and piperazine derivatives have sigma receptor activity, and suggest that compounds containing more lipophilic substituents afford greater affinity for the sigma receptor binding sites.
  • PCT publication WO 91/03243 includes a description of 1-cycloalkylpiperidines having specific antagonist activity toward sigma receptors and which are useful in the treatment of psychoses and dyskinesias.
  • PCT publication WO 93/09094 includes a description of ethers derived from alkyl piperidines or pyrrolidines which are antipsychotic agents. Additional substituted piperidines and piperazines that are sigma receptor ligands are disclosed in the PCT publication WO 94/24116.
  • the sigma receptor affinities of 1,4-(diphenylalkyl)piperazine derivatives and their use for cerebral function disorders such as dementia, depression and schizophrenia are described in U.S. Pat. No. 5,736,546.
  • No. 6,087,346 discloses certain phenylalkyl-amine, aminotetralin, piperazine, piperidine and related compounds bind to the sigma receptor, and can be used for the for the treatment of central nervous system disorders, neurological disorders, gastrointestinal disorders, drug abuse, angina, migraine, hypertension and depression.
  • Other sigma receptor ligands include BMY-14802 caramiphen and haloperidol that were found to have in vivo protective effects against NMDA-induced toxicity and seizures (M. Pontecorvo et al., (1991) Brain Res. Bull., 26:461-465).
  • Additional sigma receptor ligands include, for example, 3PP-HCl, haloperidol, allyl-normetazocine (also called SKF 10047), normetazocine, U-50488 tartrate, carbetapentane, cyclazocine, ifenprodil, DTG(1,3-Di 2tolyl guanidine), L693,409, PTPP, 4PPBP (4-phenyl-1-(4-phenylbutyl)piperidine maleate), BD 1063, IPAB iodobenzamide, SM-21, BD1008.
  • One method used to identify compounds that are ligands for the sigma receptor involves placing cells, tissues, or preferably a cellular extract or other preparation containing sigma receptors in contact with several known concentrations of a test compound in a buffer compatible with receptor activity, and assaying for ligand binding and/or receptor activity. The method can be performed either sequentially or in a multiplexed format.
  • the use of in vitro binding assays with known specific ligands can allow for the determination of ligand affinities for sigma 1 or sigma 2 receptors as described in Langa F. (2003) Eur. J. Neuroscience, 18:2188-2196.
  • Other methods for determining compounds that are ligands for the sigma receptor can be employed as will be apparent to those of skill in the art based on the disclosure herein.
  • rational drug design based upon structural studies of the molecular shapes of the sigma receptor ligands identified above and known ligands or analogs may be used to identify compounds whose three-dimensional structure is complementary to that of the active site of the sigma receptors.
  • These compounds may be determined by a variety of techniques, including molecular mechanics calculations, molecular dynamics calculations, constrained molecular dynamics calculations in which the constraints are determined by NMR spectroscopy, distance geometry in which the distance matrix is partially determined by NMR spectroscopy, x-ray diffraction, or neutron diffraction techniques.
  • the structure can be determined in the presence or absence of any ligands known to interact with sigma receptors.
  • the sigma receptor ligands thus identified or designed can be subsequently tested for their ability to treat and/or prevent neurodegenerative diseases.
  • the compounds are tested for their ability to modulate the sigma receptors, such as, for example, sigma-1 (accession numbers NM — 005866, NM — 147157, NM — 147158, NM — 147159, and NM — 147160), sigma-2, or recombinant sigma receptors.
  • Lead compounds identified during these screens can serve as the basis for the synthesis of more active analogs.
  • Lead compounds and/or active analogs generated therefrom can be formulated into pharmaceutical compositions effective in treating neurological disorders such as stroke, epilepsy and neurodegenerative disorders.
  • methods of treating a subject wherein the sigma receptor ligands I-IX, or salts or solvates thereof are administered after stroke and for a sufficient period of time necessary for treatment, such as from about 1 week to about 1 month or to about 12 months or administered continuously until the desired therapeutic effect is observed.
  • sigma receptor ligands I-IX, or salts or solvates thereof are administered after stroke and for a sufficient period of time necessary for treatment, such as from about 1 week to about 1 month or to about 12 months or administered continuously until the desired therapeutic effect is observed and wherein the subject is also exposed to a rich, stimulating environment, such as an enriched environment and to functional rehabilitation, so that functional recovery of the patient from the adverse consequences of the central nervous system injury is improved.
  • Functional recovery occurs when the functions of a damaged region of neural tissue is taken over by other areas that normally did not previously play a role in that particular function and the changes in the neural function lead to changes in behavior or in the capacity for behavior. Functional recovery is also referred to as neural plasticity. Functional recovery in the brain thus refers to functional and structural reorganization, upregulation or downregulation of a neural response to an event, and the establishment of new functional and structural connections by means of collateral sprouting and compensatory synaptogenesis as well as neurogenesis.
  • An improvement in the functional recovery of the patient can be assessed, for example, by using functional/behavioral tests to assess sensorimotor and reflex function of the patient's motor skills, such as posture, balance, grasp, or gait, cognitive skills, speech, and/or sensory perception and function including visual ability, taste, olfaction, and proprioception improve as a result of administrating the sigma receptor ligands according to the invention.
  • functional recovery of the patient can be determined by histological analysis that includes determining the length of the axonal bundles, an increase in the neuronal regeneration at the site of injury, evaluating the dendritic morphology and the number of spines, and the like.
  • the improvement in the functional recovery of the patient can be determined by using non-invasive techniques that determine structural alterations in the brain that lead to changes in neural function.
  • electrophysiological electroencephalograph (EEG) or evoked response potential (ERP)
  • EEG electromyographic
  • CSF neurochemical
  • peripheral circulating beta-endorphin levels
  • radiological CT scan, MRI
  • clinical Pupillary Light Reflex, posture, taste
  • a sigma receptor ligand is administered to mimic the effects of an enriched or stimulating environment. It is known that post-ischemic housing in an enriched or stimulating environment can improve functional outcome after brain ischemia in the rat. After an experimental brain infarction the rats housed in an enriched environment with the opportunity for various activities and interaction with other rats did better than rats housed in standard laboratory environment. An enriched environment that allowed for free physical activity combined with social interaction resulted in the best performance without change in infarct volume. An enriched environment may stimulate mechanisms that enhance brain plasticity after focal brain ischemia. It has been shown that housing rats in a stimulating environment significantly increases spine density in superficial cortical layers in intact and lesioned brain.
  • the stimulating environment comprises social interaction, motor activity, electrical stimulation of the brain, a change in the habitation, and the like.
  • the subject can be encouraged to use an impaired limb to improve sensorimotor function, may be subjected to daily physical routines, such as walking, stretching, weight lifting, and the like, or encouraged to play games, such as baseball, hockey, soccer, or board games.
  • the domicile of the subject may be changed to stimulate brain activity, such as by changing the colors in the room, providing textured material, providing items manufactured from different materials, such as wood, steel, and the like.
  • the knowledge to customize the stimulating environment for a particular patient is known to those in the physiotherapy and occupational therapy arts.
  • the stimulating environment comprises direct stimulation of the brain or a region of the brain.
  • electrical impulses can be applied to the brain as described in U.S. Pat. Nos. 6,339,725, and 5,611,350, and other methods known in the art.
  • the brain or a region of the brain can be stimulated by localized administration of drugs, such as acetylcholine, nerve growth factors, such nerve stimulating agents, neuronal or glial growth factors and other neuronal modulating drugs.
  • the timing of administering the dosage containing the sigma ligands can vary.
  • the sigma receptor ligands are administered after a stroke.
  • the administration of the ligands can be initiated within the first week of the onset of the symptoms, preferably at least 24 hours, or at least 48 hours of the onset of the symptoms.
  • the sigma receptor ligands are administered to the patient concurrently with exposure to a stimulating environment.
  • the sigma receptor ligands are administered after a stroke at a time when the patient is subjected to a stimulating environment, and the ligands are administered for about 1 month to about 3 months to facilitate functional recovery.
  • the ligands, and compositions comprising the ligands are administered up to about 12 months or longer, or, even more preferably, administered continuously.
  • compositions comprising the molecules described above, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • excipients include liquids such as water, saline, glycerol, polyethyleneglycol, hyaluronic acid, ethanol, etc. Suitable excipients for non-liquid formulations are also known to those of skill in the art.
  • compositions of the present invention include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like
  • organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • a biological buffer can be virtually any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range.
  • buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank's buffered saline, and the like.
  • the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention including isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and/or prophylactic ingredients.
  • the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of this invention for a given disease.
  • compounds of this invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • oral including buccal and sub-lingual
  • rectal including nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • parenteral including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous administration or in a form suitable for administration by inhalation or insufflation.
  • the preferred manner of administration is intravenous or oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • the composition will generally take the form of a tablet, capsule, a softgel capsule or may be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • the compounds of the invention can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • capsules can be prepared by conventional procedures so that the dosage unit is 100 mg of the compounds of the invention, 100 mg of cellulose and 10 mg of magnesium stearate.
  • a large number of unit capsules may also prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 10 mg magnesium stearate.
  • tablets may be prepared by conventional procedures so that the dosage unit is 100 mg of the compounds of the invention, 150 mg of lactose, 50 mg of cellulose and 10 mg of magnesium stearate.
  • a large number of tablets may also be prepared by conventional procedures such that the dosage unit was 100 mg of the compounds of the invention, and other ingredients can be 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 250 mg of microcrystalline cellulose, 10 mg of starch and 100 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • the active agent may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well.
  • suitable inert carrier such as ethanol, glycerol, water, and the like
  • flavoring, coloring and/or sweetening agents may be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation may also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration may involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • aqueous and non-aqueous, isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certain parenteral routes can involve introducing the formulations of the present invention into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as an continuous infusion system.
  • a formulation provided by the present invention can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
  • the formulations can optionally contain an isotonicity agent.
  • the formulations preferably contain an isotonicity agent, and glycerin is the most preferred isotonicity agent.
  • concentration of glycerin, when it is used, is in the range known in the art, such as, for example, about 1 mg/mL to about 20 mg/mL.
  • the pH of the parenteral formulations can be controlled by a buffering agent, such as phosphare, acetate, TRIS or L-arginine.
  • concentration of the buffering agent is preferably adequate to provide buffering of the pH during storage to maintain the pH at a target pH ⁇ 0.2 pH unit.
  • the preferred pH is between about 7 and about 8 when measured at room temperature.
  • additives such as a pharmaceutically acceptable solubilizers like Tween 20® (polyoxyethylene (20) sorbitan monolaurate), Tween 40® (polyoxyethylene (20) sorbitan monopalmitate), Tween 80® (polyoxyethylene (20) sorbitan monooleate), Pluronic F68® (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) can optionally be added to the formulation, and may be useful if the formulations will contact plastic materials.
  • the parenteral formulations can contain various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating one or more of the compounds of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • compositions of the invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable nonirritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of the invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
  • Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives.
  • Creams containing the selected active agent are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil.
  • Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • the specific ointment or cream base to be used is one that will provide for optimum drug delivery.
  • an ointment base should be inert, stable, nonirritating and nonsensitizing.
  • Formulations for buccal administration include tablets, lozenges, gels and the like.
  • buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art.
  • the compounds of the invention may also be delivered through the skin or muscosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface.
  • the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer.
  • the laminated device may contain a single reservoir, or it may contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or gel reservoir, or may take some other form.
  • the backing layer in these laminates which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility.
  • the material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present.
  • a pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject.
  • the precise effective amount will vary from subject to subject and will depend upon the species, age, the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration.
  • the effective amount for a given situation can be determined by routine experimentation.
  • a therapeutic amount will be in the range of about 0.01 mg/kg to about 40 mg/kg body weight, more preferably about 0.1 mg/kg to about 10 mg/kg, in at least one dose.
  • the indicated daily dosage can be from about 1 mg to 300 mg, one or more times per day, more preferably in the range of about 10 mg to 200 mg.
  • the subject may be administered as many doses as is required to reduce and/or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system.
  • the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the invention in another aspect, relates to pharmaceutical compositions in kit form.
  • the kit comprises container means for containing the compositions such as a bottle, a foil packet, or another type of container.
  • the kit further comprises directions for the administration of the compositions.
  • a packaged kit contains the pharmaceutical formulation to be administered, i.e., a pharmaceutical formulation containing a ligand for the sigma receptor for the treatment of a neurodegenerative disease to facilitate neuronal regeneration or functional recovery, a container, preferably sealed, for housing the formulation during storage and prior to use, and instructions for carrying out drug administration in a manner effective to treat the disease.
  • the instructions will typically be written instructions on a package insert and/or on a label.
  • the formulation may be any suitable formulation as described herein.
  • the formulation may be an oral dosage form containing a unit dosage of the ligand for the sigma receptor.
  • the kit may contain multiple formulations of different dosages of the same agent.
  • the kit may also contain multiple formulations of different active agents.
  • kits for parenteral administration can comprise a) a pharmaceutical composition comprising one or more of the compounds described above and a pharmaceutically acceptable carrier, vehicle or diluent; and, optionally, b) instructions describing a method of using the pharmaceutical composition for treating or preventing the disease.
  • the kits can further include a device for administering the formulation (e.g., a syringe, a catheter, and the like).
  • the kits for oral administration can comprise the dosage formulation contained within a container, such as, for example, a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag, or a blister pack with individual doses.
  • Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • a foil of a preferably transparent plastic material During the packaging process, having recesses the size and shape of the tablets or capsules, are formed in the plastic foil. Subsequently, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via the opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the dosage form so specified should be administered.
  • a memory aid is a calendar printed on the card e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.
  • memory aids such as, for example, a mechanical counter which indicates the number of daily doses that has been dispensed, a microchip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken, and the like.
  • SHR spontaneous hypertensive rats
  • MCA occlusion Male 3 months old SHR (spontaneous hypertensive) rats are used for induction of stroke by MCA occlusion. This is the preferred strain since most stroke patients are hypertensive.
  • the animals are anesthetized with Methohexital and a small craniectomy is made above the zygmotic arch to expose the middle cerebral artery, which is occluded with a 10-0 monofilament nylon thread distal to the origin of the striatal branches.
  • the rats are not intubated and no catheters are inserted. Following MCA occlusion a large and reproducible infarct is obtained, leading to a robust sensorimotor deficit.
  • the animals are kept on a 6 hr light/18 h dark cycle with free access to food and water.
  • the rats are treated with the compound I, II, III, IV, V, VI, VII, VIII, or IX (0.03-10 mg/kg) s.c. or p.o. and a control group is given saline for 2-8 weeks.
  • a control group is given saline for 2-8 weeks.
  • animals are tested in the rotating pole or cylinder test
  • Rotating pole This test allows for the rapid assessment of coordination and integration of motor movement, by the ability of the rat to traverse a rotating pole as described previously (Johansson and Ohlsson, (1995) Stroke 26: 644-649.
  • the pole has a length of 1500 mm, is elevated 750 mm above the floor and rotates at 10 rpm to the right or left, respectively.
  • a score of 6-0 is given for each direction:
  • the animal crosses the pole with more than 50% foot slips
  • the cylinder test (modified from Schallert and Tillerson (Innovative models of CNS disease: from molecule to therapy. Clifton, N.J., Humana, 1999) is used to quantify the forelimb use for rearing on the cylinder wall.
  • the rats are monitored as they move freely in a 20-cm-wide clear glass cylinder.
  • Contacts made by each forepaw with the cylinder wall while rearing are scored by a blinded observer. A total of 20 contacts are recorded for each animal, and the number of impaired (left), both, and non-impaired forelimb contacts as percentage of total contacts is calculated.
  • Baseline for rats is achieved by measuring the contacts made by each forepaw before MCAO.
  • the group of animals that are given compounds I, II, III, IV, V, VI, VII, VIII, or IX perform better than the group 1 control animals.
  • animals suffering from central nervous system disorders show enhanced functional recovery when administered sigma receptor ligands.
  • this test demonstrates that the sigma-1 selective agonist, SA4503 facilitates functional recovery, in particular recovery in a motor skill, when administered daily to rats in a model of ischemic stroke from 2 days after the stroke until 28 days after the stroke for 28 days.
  • MCAO middle artery occlusion
  • the rats were monitored as they moved freely in a 20 cm-wide clear glass cylinder. Contacts made by each forepaw with the cylinder wall while rearing were scored by a blinded observer. A total of 20 contacts were recorded for each animal, and the number of impaired (left), both, and non-impaired forelimb contacts as a percentage of total contacts was calculated. The results are given in Table 2.
  • this test demonstrates that the sigma-1 selective agonist, SA4503 facilitates functional recovery, in particular recovery in a motor skill, when administered daily to rats in a model of ischemic stroke from 2 days after the stroke for 14 days.
  • the Morris water maze was used to assess functional recovery, in-particular recovery in a cognitive skill, in spontaneously hypertensive rats after exposure to permanent middle artery occlusion (MCAO), a model of ischemic stroke.
  • MCAO middle artery occlusion
  • MCAO middle artery occlusion
  • the rats were given a series of 6 trials, 1 hour apart in a large dark-colored tank (200 cm in diameter) filled with clear water at a temperature of 22.0 ⁇ 1.5° C.
  • a 12 ⁇ 12-cm submerged platform (2 mm below the water surface) was placed in the northwest quadrant of the pool. The release point was always the southern end of the pool.
  • the rats were lowered into the pool facing the wall, and then released.
  • Each rat was given a maximum of 90 seconds to find the submerged platform. If it did not find the platform in that time, the rat was physically guided to it. After remaining on the platform for 20 seconds, the rat was removed and placed in a dry cage.
  • each rat was given a second trial, using the same release position and platform position, to measure the rat's retention of the platform location. The process was repeated a total of 5 times for each rat, each trial 1 hour apart.
  • the swim paths of the rats were recorded with a computer tracking system and the latency and the length of swim path to find the hidden platform were analyzed.
  • the latency to find the hidden platform (in seconds) is given in Table 3.
  • the length of swim path to find the hidden platform is given in Table 4.
  • rats Postoperatively, rats were kept in individual cages for 24 hours.
  • the rats subjected to MCA occlusion (MCAO) were either returned to standard environment (SE), or were placed in a large,.vertical, enriched-environment (EE) cage (815 ⁇ 610 ⁇ 1,280 mm), equipped with horizontal and vertical boards, chains, swings, wooden blocks, and objects of different sizes and materials. The distance between the boards and the movable objects was changed twice a week.
  • the sham group were subjected to a sham surgery without MCAO and placed in the standard environment. In all experimental groups 12 and 60 days of recovery were selected as end point analysis of gene expression. The study was conducted using 6 experimental groups, with each group composed of 6-8 animals.
  • cDNA arrays consisting of 50,000 clones from a rat cortex cDNA library were hybridized with labeled target nucleic acid obtained from control, standard MCAO and enriched environment animals. About 3400 upregulated genes were selected after bioinformatics analysis of the resulting gene discovery array data. The raw clone data was normalized by the median empty well value for each respective array filter. These values were then transformed (log 2+1) to approximate normality. All replicates where then pooled for subsequent statistical analysis.
  • the time points of the three experimental conditions where analyzed by principal component analysis (PCA).
  • PCA principal component analysis
  • the outlying data points where removed from the data set.
  • an ANOVA was performed with regard to a clone's behavior among the experimental conditions within a given brain region and time point.
  • the results of the ANOVA were filtered for clones that had a p-value less than 0.05. This filtered ANOVA list was then analyzed with the Tukey HSD test to determine the clone's expression pattern.
  • Selection was based on expression upregulation of ⁇ 1.8-fold and a coefficient of variation (cv) of ⁇ 0.2.
  • the selected clones were picked, amplified by PCR, and re-printed on nylon membranes for profiling arrays.
  • the profiling arrays were probed with probes from different cortical and subcortical regions and recovery times of 12 and 60 days. Clones that were upregulated were selected for further analysis.
  • type 1 sigma receptor mRNA is upregulated while in medial cortex, type 1 sigma receptor mRNA is downregulated when the animals were placed in an enriched compared to standard environment.
  • stimulation of brain by application of an enriched environment induces expression of the type 1 sigma receptor in brain regions important for control of sensory-motor functions.
  • the middle cerebral artery occlusion (MCAO) model is a well accepted model of a focal ischemic episode or stroke (Gotti, et al., (1990) Brain Res. 522: 290-307).
  • Focal ischemia is produced by obstructing blood flow through the MCAO, resulting in infarction of the brain locus supplied by this artery.
  • the MCAO model is reasonably predictive of the ability and efficacy of drugs, such as sigma receptor ligands, to alter functional recovery in humans in whom central nervous system tissue has been damaged or lost due to stroke.
  • the MCAO model is deemed reasonably predictive of drug efficacy to restore or detectably improve motor coordination, sensory perception, speech or any other central nervous system function naturally contributed to by tissue within the territory of the MCAO.
  • Rats are divided into two groups, with each group containing about 8 rats. Rats in each group were subjected to MCAO. Group 1 is used as a control and receives no treatment. Group 2 is housed under standard conditions and administered fluvoxamine, a sigma receptor ligand. At 2, 4, and 8 weeks animals are then subjected to the rotating pole test to assess functional recovery.
  • Rotating pole This test allows for the rapid assessment of coordination and integration of motor movement, by the ability of the rat to traverse a rotating pole as described previously (Johansson and Ohlsson, (1995) Stroke 26: 644-649.
  • the pole has a length of 1500 mm, is elevated 750 mm above the floor and rotates at 10 rpm to the right or left, respectively.
  • a score of 6-0 is given for each direction:
  • the animal crosses the pole with more than 50% foot slips
  • Food reaching test assesses the fine motor function of the animals.
  • the animals are first tested for limb preference prior to MCAO.
  • the rat is then placed in a restricted plexiglass box with only a slit in the front where the rat can reach for the pellet.
  • the time it takes for the rat and the way the rat grasps for the pellet is recorded on video and scored.
  • Forelimb flexion The animal is suspended by the tail and lowered quickly to the surface level. A score of 4 is set if the animal had a smooth and controlled flexion with finger movement. A score of 0 is set if the animals nose touched the surface without any forelimb flexion.
  • Hindlimb flexion When raised by the tail, the rats exhibit a characteristic backward and lateral extension of the hindlimbs and spreading of toes. A score of 3 is set if the hindlimbs showed extension with toe spread and a score of 0 is set if there was no hindlimb flexion or toe spread.
  • the group 2 animals that are given fluvoxamine perform better than group 1 animals.
  • animals suffering from central nervous system disorders show enhanced functional recovery when administered sigma receptor ligands.
  • the compound of formula IV (10.0 g) is mixed with lactose (85.5 g), hydroxypropyl cellulose HPC-SL (2.0 g), hydroxypropyl cellulose L-HPC, LH-22 (2.0 g) and purified water (9.0 g), the resulting mixture is subjected to granulation, drying and grading, and the thus obtained granules are mixed with magnesium stearate (0.5 g) and subjected to tablet making, thereby obtaining tablets containing 10 mg per tablet of the compound of formula IV.
  • the tablet prepared in Example 6 is provided to a subject at time 0. One tablet every 24 h is provided for a period of one week. After administration of the third tablet, the subject is exposed to a neurodegenerative event. The treated subject exhibits symptoms of neurological disorder that are less severe compared to the subject that was not treated.

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US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
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US20050059689A1 (en) * 2003-06-12 2005-03-17 Donna Oksenberg Sigma ligands for neuronal regeneration and functional recovery
US20090156637A1 (en) * 2004-11-03 2009-06-18 University Of North Texas Health Science Center Of Fort Worth Butyrophenones and sigma-1 receptor antagonists protect against oxidative-stress
US20070123556A1 (en) * 2005-06-06 2007-05-31 University Of South Florida Treatment with Sigma Receptor Agonists Post-Stroke
WO2007078618A2 (fr) * 2005-12-16 2007-07-12 Vela Acquisition Corporation Traitement de la douleur au moyen de 1-[3-[4-(3-chlorophényl)-1-pipérazinyl]propyl]-5-méthoxy-3,4-dihydro-2(1h)-quinolone ou d'un sel de ce composé
WO2007078618A3 (fr) * 2005-12-16 2008-01-24 Vela Acquisition Corp Traitement de la douleur au moyen de 1-[3-[4-(3-chlorophényl)-1-pipérazinyl]propyl]-5-méthoxy-3,4-dihydro-2(1h)-quinolone ou d'un sel de ce composé
US20110052723A1 (en) * 2008-02-18 2011-03-03 Baeyens-Cabrera Jose Manuel Use of compounds binding to the sigma receptor ligands for the treatment of neuropathic pain developing as a consequence of chemotherapy
US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
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US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
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US20160151311A1 (en) * 2012-05-02 2016-06-02 University Of South Florida N,n'-di-1 naphthylguanidine hcl (nagh) and n,n'-di-p-nitrophenylguanidine hcl (nad) treatment for stroke at delayed timepoints
US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
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US11364361B2 (en) 2018-04-20 2022-06-21 Neuroenhancement Lab, LLC System and method for inducing sleep by transplanting mental states
EP3844171A4 (fr) * 2018-08-31 2022-08-10 Texas Tech University System Amplificateurs de l'activité de la neurolysine
US11452839B2 (en) 2018-09-14 2022-09-27 Neuroenhancement Lab, LLC System and method of improving sleep
WO2023154794A1 (fr) * 2022-02-09 2023-08-17 University Of North Texas Health Science Center Repositionnement de médicament pour le traitement différé d'un accident vasculaire cérébral ischémique

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US20050059689A1 (en) 2005-03-17
WO2004110387A2 (fr) 2004-12-23
WO2004110387A3 (fr) 2005-08-18
WO2004110389A3 (fr) 2005-12-22
CA2528160A1 (fr) 2004-12-23
JP4963607B2 (ja) 2012-06-27
EP1644026A2 (fr) 2006-04-12
EP1635805A4 (fr) 2007-08-08
JP2007500757A (ja) 2007-01-18
EP1635805A2 (fr) 2006-03-22
EP1644026A4 (fr) 2007-10-24
US7863272B2 (en) 2011-01-04
WO2004110389A2 (fr) 2004-12-23
WO2004110388A2 (fr) 2004-12-23
CA2528160C (fr) 2012-01-03
WO2004110388A3 (fr) 2005-07-28
US20110082154A1 (en) 2011-04-07
US20050032827A1 (en) 2005-02-10

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