WO2016138135A1

WO2016138135A1 - Sigma-1 receptor modulators for treating huntington's disease

Info

Publication number: WO2016138135A1
Application number: PCT/US2016/019365
Authority: WO
Inventors: Ferdinando SQUITIERI; Alba DI PARDO
Original assignee: Teva Pharmaceuticals International Gmbh; Teva Pharmaceuticals Usa, Inc.
Priority date: 2015-02-25
Filing date: 2016-02-24
Publication date: 2016-09-01

Abstract

This invention provides a method of treating a subject suffering from a neurodegenerative disease or neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a modulator of the Sigma-1 receptor so as to thereby treat the subject.

Description

S IGMA-1 RECEPTOR MODULATORS FOR TREATING HUNTINGTON'S

DISEASE

This application claims the priority of U.S. Provisional Application No. 62/120,736, filed February 25, 2015, the content of which is hereby incorporated by reference.

Throughout this application, various publications are referenced, most typically by the last name of the first author and the year of publication. Full citations for these publications are set forth in a section entitled References immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the invention relates. BACKGROUND OF THE INVENTION

Huntington's disease (HD) is a neurodegenerative, dominantly transmitted disease whose single HTT gene mutation results in the synthesis of mutant huntingtin (mHtt) , a misfolded protein with an expanded polyglutamine stretch in the N-terminus (Huntington's Disease Collaborative Research Group 1993) . The resulting mutant protein causes a cascade of toxic events in the nervous system which lead to neuronal cell dysfunction and death (Sari 2011) . The wide range of HD- related cellular and neurochemical alterations result in a complex and progressively disabling phenotype, in which hyperkinetic (i.e. chorea and dystonia) and hypokinetic (i.e. parkinsonisms such as bradykinesia and rigidity) clinical manifestations coexist throughout the disease course (Kirkwood 2001) . Hyperkinesias generally predominate at the beginning of the clinical course, whilst parkinsonisms are more often observed in the advanced stages of HD (Kirkwood 2001) . The clinical complexity of such conditions seems to be linked to aberrant dopamininergic transmission in HD (Andre 2010, Chen 2013) and represents a challenge for effectively treating the disease.

BRIEF SUMMARY OF THE INVENTION

The invention also provides a method of treating a subject suffering Huntington's disease comprising administering to the subject a therapeutically effective amount of a modulator of the Sigma-1 receptor so as to thereby treat the subject.

The invention also provides a modulator of the Sigma-1 receptor for use in treating a subject suffering from a neurodegenerative disease or neurodegenerative disorder.

The invention also provides use of a modulator of the Sigma-1 receptor in the manufacture of a medicament for treating a subject suffering from a neurodegenerative disease or neurodegenerative disorder.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Figure 1. Chronic administration of pridopidine (5mg/kg) improves motor function and prolongs lifespan in pre- symptomatic R.6/2 mice. (A) Analysis of motor coordination on horizontal ladder task before and after the treatment in 5 week-old R6/2 mice and WT littermates. (B) General locomotor activity in the open field in the same mice, before and after treatment. Each data point represents the average performance ± SD of 8- 10 mice for each group. **, p<0.001; p<0.0001 (vehicle-treated R6/2 vs pridopidine-treated R6/2); ^###, p<0.001 (vehicle-treated WT vs vehicle-treated R6/2); ^$, p<0.05; ^?$, p<0.01 (pridopidine-treated WT vs pridopidine-treated R6/2) , (Two-way ANOVA with Bonferroni posttest) . (C) Kaplan-Meier probability of survival analysis in pridopidine- and vehicle-treated R6/2 mice. N=8-10 mice for each group **, p<0.01 (Log- Rank Test) . Figure 2. Chronic administration of pridopidine (5mg/kg) transiently improves motor function in symptomatic R6/2 mice. Analysis of motor coordination on the horizontal ladder task before and after the dosage change in 7 week-old R6/2 mice and WT littermates. Each data point represents the average performance ± SD of 8 mice for each group. ^##, p<0.001 (vehicle-treated R6/2 vs pridopidine-treated R6/2); * p<0.05; ** p<0.001; ***, p<0.0001; (vehicle- and pridopidine-treated WT vs vehicle-treated R6/2), (Two-way ANOVA with Bonferroni post test) .

Figure 3. Pridopidine enhances the expression of both BDNF and DARPP32 in the striatum of R6/2 mice. (A)

Representative Western Blotting and densitometric analysis of BDNF and (B) DARPP32 protein in striatal tissues from WT littermates and R6/2 mice before and after the treatment. Data are represented as mean ± SD, n = 5 for each group of mice. *, p<0.05; **, p<0.001 (Non-parametric Mann Whitney U) . Figure 4. Pridopidine induces remodelling of mHtt aggregates. (A) Representative micrograph of E 48 positive striatal mHtt aggregates from vehicle- and pridopidine-treated R6/2 mice. Arrows indicate mHtt aggregates (scale bar 25μπι) . (B) Semiquantitative analysis of mHtt aggregates size (area) . (C) Western Blotting Data are represented as mean ± SD. n = 5 for each group of mice. ***, p<0.0001 (two-tailed t-test) . (C) Immunoblotting for EM48 positive mHtt aggregates in the stacking gel in protein extracts from Wt and R6/2 striatal brain tissues before and after the administration of pridopidine.

Figure 5. Administration of pridopidine protects HD striatal-derived cell lines from apoptosis and promotes ERK activation. (A) Apoptosis in STHdh cell line cultured for six hours in serum-free medium in presence or absence of 150 μΜ pridopidine and /or NE100. Data are represented as mean ± SD of three experiments, each performed in triplicate. *, p<0.05; **, p<0.001 (Non- parametric Mann Whitey U) . (B) Representative Western Blotting of ERK phosphorylation in protein extracts from cells treated or not with pridopidine and/or NE100. (C) Immunoblotting for EM48 positive mHtt aggregates in the stacking gel in cell lysates cultured in presence or absence of pridopidine and /or NE100. Figure 6. Chronic administration of pridopidine at constant dose fails to enhance cerebral expression of both BDNF and DARPP32. (A) and (B) Representative Western Blottings and densitometric analyses of BDNF protein expression in striatal and cortical tissue of vehicle- and pridopidine-treated R6/2 mice. Data are represented as mean + SD, n=5 for each group of mice. Average brain weight of 11 week-old vehicle- and FTY720 -treated WT and R6/2 mice, vehicle- and FTY-treated T mice n=5 for each group; vehicle-treated R6/2 mice n=8; FTY720-treated mice n=7, *, p<0.05; **, p<0.001 (Non- parametric Mann Whitey U) . (C) Representative Western Blotting and densitometric analysis of DARPP32 in striatal tissues of the same mice. Data are represented as mean ± SD. n=5 for each group of mice.

Figure 7. Change of pridopidine dose does not increase expression of BDNF in the cortex of R6/2 mice. Representative Western Blotting in cortical tissue of vehicle- and pridopidine-treated R6/2 mice. Data are represented as mean ± SD, n=5 for each group of mice.

Figure 8. Chronic administration of pridopidine fails to prevent loss of brain weight in R6/2 mice. Average brain weight of vehicle- and pridopidine -treated WT and R6/2 mice. Vehicle- and pridopidine-treated WT mice n=5 for each group; vehicle-treated R6/2 mice n=7; pridopidine- treated mice n=7, **, p<0.001 (Non-parametric Mann Whitey U)

Figure 9. Pridopidine (150uM) resulted to be the e fective dose in protecting HD cells rom apoptosis .

Apoptosis in striatal-derived cell lines cultured for six hours in serum free medium in presence or absence of different concentrations of pridopidine. Data are represented as the mean ± SD of two independent experiments performed in quadruplicate. *, p<0.05; **, p<0.001 (non parametric Mann Whitney U) Figure 10. Dose-dependent reduction of early ER stress by pridopidine. A, B. H2aGFP was transiently coexpressed with Htt96Q-cherry (exon 1) in STHdhQl/l cells. Cells were treated without (A) or with 50 μg/ .l pridopidine (B) starting 4h post-transfection and H2aGFP and Htt96Q- cherry were imaged in a confocal microscope 24h post- transfection . Representative images of cells with aggregated or non-aggregated Htt96Q-cherry as indicated are shown. C. Images of individual cells (~150 cells per experiment) with aggregates were quantified compared to untreated cells with and without aggregates. 100% represents H2aGFP relative intensity in untreated cells showing Htt96Q-cherry aggregates, 0% is H2aGFP relative intensity in untreated cells without Htt96Q-cherry aggregates. The graph is an average of 3 experiments +- SD. The asterisks indicate P values compared to untreated, 0.011, 0.009, 0.006 and 0.026 respectively. D. A similar experiment but with expression of Htt20Q- cherry. In this case 100% represents H2aGFP. relative intensity in untreated cells with Htt96Q-cherry aggregates analyzed in parallel in each experiment. The graph is an average of 3 experiments +-SD. P value (0.01 vs. 0) = 0.036.

Figure 11. Lack of effect of pridopidine on Htt96Q- cherry aggregation. The number of cells with Htt96Q- cherry aggregates was counted in the experiment of Figure IOC, and the percent calculated relative to the total. The graph is an average of 3 experiments +-SD. Figure 12. Effect of Htt96Q~cherry aggregation on Sigma- 1R-GFP. Sigma-lR-GFP was transiently coexpressed with Htt20Q-cherry (left panels) or Htt 96Q-cherry (middle and right panels) in ST#dhQ7/7 cells, left untreated or treated with 50 pridopidine (right panels) . Representative images of cells are shown.

Figure 13. Pridopidine increases Sigma-1R-GFP levels in the presence of Htt96Q-cherry aggregates .

(A) Sigma-IR-GFP was transiently coexpressed with Htt96Q-cherry in STHdh^Q1/Ί cells. Sigma-IR-GFP intensity was quantified in individual cells with Htt96Qcherry aggregates compared to cells with no aggregates. The graph is an average of 3 experiments +-SD. P value = 0.023. (B) Cells were treated with the indicated concentrations of pridopidine starting 4h post- transfection . Sigma-IR-GFP levels were quantified in images of individual cells (~150 cells per experiment) with Htt96Q-cherry aggregates compared to untreated cells with and without aggregates. 100% represents Sigma-IR-GFP relative intensity in untreated cells without Htt96Q-cherry aggregates. The graph is an average of 3 experiments +-SD. P value (50 vs. 0) = 0.034. (C) A similar experiment but with expression of Htt20Q-cherr . The graph is an average of 3 experiments +-SD.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the neurodegenerative disease or neurodegenerative disorder is related to the Sigma-1 receptor. In another embodiment, the neurodegenerative disease or neurodegenerative disorder is a neurodegenerative disease or neurodegenerative disorder other than Huntington's disease. In another embodiment, the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of methamphetamine addiction, cocaine addiction, alcohol addiction, pain, mood disorder, major depressive disorder, psychotic or delusional major depression, Alzheimer's disease, HIV infection,

Schizophrenia, Parkinson's disease, parkinsonian, anxiety disorders, obsessive-compulsive disorder, stroke, and age- related cognitive impairments.

In another embodiment, the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of neuropsychiatric diseases, amnesia, neuropathic pain depression, retinal neuroprotection, Pseudobulbar effect, familial adult amyotrophic lateral sclerosis (ALS) , juvenile amyotrophic lateral sclerosis (ALS) , multiple sclerosis (MS), glaucoma, and cancer.

In an embodiment, treating the neurodegenerative disease or neurodegenerative disorder comprises providing neuroprotection in the subject. In another embodiment, treating the neurodegenerative disease or neurodegenerative disorder comprises delaying neurodegeneration in the subject.

This invention also provides a method of treating a subject suffering Huntington's disease comprising administering to the subject a therapeutically effective amount of a modulator of the Sigma-1 receptor so as to thereby treat the subject.

In an embodiment, treating the neurodegenerative disease or neurodegenerative disorder comprises delaying neurodegeneration in the subject. In another embodiment, treating the neurodegenerative disease or neurodegenerative disorder comprises providing neuroprotection in the subject.

In an embodiment, the modulator is not pridopidine.

In an embodiment, the modulator of the Sigma-1 receptor is an agonist of the Sigma-1 receptor.

In an embodiment, the modulator is at least one member of a group comprising: SA4503 (Cutamesine) , (+) -pentazocine) , (-)- Pentazocine, (+)-SKF 10047, clorgyline, Fluoxetine,

Fluvoxamine, imipramine, Carbetapentane, Dextromethorphan, Dextrorphan, Dimemorfan, amantadine, donepezil, memantine, neurosteroid dehydroepiandrosterone-sulfate (DHEA-S) ,

Pregnenolone sulfate, BD 737, 4-IBP, (+) -Igmesine, OPC-14523, (+) -3- (3-Hydroxyphenyl) -N- (1-propyl) -piperidine, PRE-084, (±)-PPCC oxalate, ANAVEX 2-73, DMT (N, -Dimethyltryptamine) , ANAVEX 1-41, DHEA BD1031, BD1052, Pentoxyverine , UMB23, UMB 1 , UMB82, Ditolylguanidine , 4-phenyl-1- ( 4- phenylbutyl) iperidine) and ANAVEX 3-71.

In another embodiment, the modulator is at least one member of a group comprising: Chlorpromazine, Nemonapride, Sertraline, Phenytoin (DPH) , Ropizine, ( (-) -SKF-10047 ) , N-[2- (Piperidinylamino) ethylj -4-iodobenzamide, Allylnormetazocine, testosterone, pregnenolone, nemopramide, Eliprodil

(SL82.0715), LS-127, LS-137, SV 89, SV 156, pimozide, propranolol, TC 1, SKF 83959, PD144418, Afobazole, Citalopram, Escitalopram, etamine, L-687,384, methylphenidate, Opipramol, and Quetiapine.

In another embodiment, the modulator is at least one member of a group comprising: NE100, AC927, AZ66, BD1008, BD-1047, BD1060, BD1067, LR132, MS-377, progesterone , BD1063, BMY- 14802 and E-52862.

In another embodiment, the modulator is at least one member of a group comprising: UMB 100, UMB 101, UMB 103, YZ-069, NE100, AC927, AZ66, BD1008, BD-1047, BD1060, BD1067, LR132, haloperidol, reduced haloperidol, Rimcazole, Panamesine, YZ- 011, Dup 734, (+)-MR 200, Metaphit, MS-377, progesterone, BD1063, SSR125047, SR31742, AC927, BMY-14802, S1RA, ΆΖ66, CM156, E-5842, LR172, UMB 116, and YZ-185. The invention also provides a modulator of the Sigma-1 receptor for use in treating a subject suffering from a neurodegenerative disease or neurodegenerative disorder.

Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. For instance, the elements recited in the method embodiments can be used in the use embodiments described herein and vice versa. Thus, all combinations of the various elements described herein are within the scope of the invention.

TERMS As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below .

"Administering to the subject" means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject to relieve or cure a pathological condition. Oral administration is one way of administering the instant compounds to the subject. As used herein, "about" in the context of a numerical value or range means +10% of the numerical value or range recited.

As used herein, an "amount" of a compound as measured in milligrams refers to the milligrams of compound present in a preparation, regardless of the form of the preparation. An ^N>amount of compound which is 40 mg" means the amount of the compound in a preparation is 40 mg, regardless of the form of the preparation. Thus, when in the form with a carrier, the weight of the carrier necessary to provide a dose of 40 mg compound would be greater than 40 mg due to the presence of the carrier .

As used herein, the terms "inhibiting, " "inhibit" or "inhibition" of any binding means preventing or reducing the interaction.

As used herein, the term "pridopidine" refers to pridopidine free base. In certain embodiments, pridopidine also includes any pharmaceutically acceptable salt, such as the HC1 salt. Preferably, in any embodiments of the invention as described herein, the pridopidine is in the form of its hydrochloride salt .

The terms "Treat" or "Treating, " a disorder/disease shall mean slowing, stopping or reversing the disorder's progression, and/or ameliorating, lessening, or removing symptoms of the disorder. Thus treating a disorder encompasses reversing the disorder's progression, including up to the point of eliminating the disorder itself . used herein, the term "effective amount" refers the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit /risk ratio when used in the manner of this invention, i.e. a therapeutically effective amount. The specific effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compounds or its derivatives.

As used herein, "a modulator of the Sigma-1 receptor" or "a Sig-IR modulator" is a compound which affects the Sigma-1 receptor in any way, including but not limited to a compound which stimulates, inhibits or stabilizes the Sigma-1 receptor. An example of a modulator of the Sigma-1 receptor is pridopidine. A modulator may be an agonist or an antagonist. The modulators of the present invention, including any now known or later discovered, also may be natural or synthetic.

As used herein, "an agonist of the Sigma-1 receptor" or ^ya Sig-IR agonist" is one which causes the specific stimulation or activation of the Sigma-1 receptor activation. In an embodiment, the specific agonists acts the same as a ligand for the Sigma-1 receptor. Cobos 2008 identifies the following Sig-IR agonists: SA4503 (cutamesine) , (+)isoform of pentazocine ((+)- pentazocine), (-) -Pentazocine, (+)-SKF 10047, clorgyline, Fluoxetine, Fluvoxamine, imipramine, Carbetapentane, Dextromethorphan, Dextrorphan,

Dimemorfan, amantadine, donepezil, memantine, neurosteroid dehydroepiandrosterone-sulfate (DHEA-S) , Pregnenolone sulfate, BD 737, 4-IBP, (+) -Igmesine, OPC- 14523, (+J-3-PPP ( (+) -3- (3~Hydroxyphenyl) -N- (1-propyl) - piperidine) , and PRE-084. Hajipor 2009 identifies the following Sig-lR agonists: (±)-PPCC oxalate, ANAVEX 2- 73, and DMT (N, -Dimethyltryptamine) . Maurice 2009 identifies the following Sig-lR agonists: ANAVEX 1-41 and DHEA ( Dehydroepiandrosterone) . Matsumoto 2001 identifies the following Sig-lR agonists: BD1031 and BD1052. Wang 2007 identifies the following Sig-lR agonists: Pentoxyverine, UMB23, UMB41, and UMB82. Other known Sig-lR agonists are Ditolylguanidine (DTG) (Katnik 2006), 4-PPBP (4-phenyl-l- (4-phenylbutyl) piperidine) (Ishikawa 2010) and ANAVEX 3-71 (Francardo 2014) . Other examples include related analogs of any of the aforementioned agonists.

Cobos 2008 identifies the following Sig-lR modulators: Chlorpromazine, Nemonapride, Sertraline, Phenytoin

(DPH), Ropizine, ( (-) -SKF-10047 ) , N-[2-

(Piperidinylamino) ethyl] -4-iodobenzamide,

Allylnormetazocine, testosterone, pregnenolone, nemopramide, and Eliprodil (SL82.0715). Luedtke 2011 identifies the following Sig-lR modulators: LS-127, LS- 137, SV 89, SV 156, pimozide, and propranolol. The following Sig-lR modulators are available from Tocris Bioscience: TC 1, SKF 83959, and PD144418. Other known Sig-lR modulators are Afobazole (Cuevas 2011) , Citalopram (Ishima 2014), Escitalopram (Ishima 2014), Ketamine (Robson 2012), L-687,384 (McLarnon 1994), methylphenidate (Zhang 2012) , Opipramol (Rao 1990) , and Quetiapine (Kotagale 2013). Also included as modulators of the Sig-lR are Sig-IR agonists and Sig-IR antagonists . As used herein, a selective antagonist of the Sigma-1 receptor is one which causes the specific inhibition of or the specific interference with Sigma-1 receptor activation. The preferred example of a selective antagonist of the Sigma-1 receptor is NE100 (4-Methoxy- 3- (2-phenylethoxy) -N, -dipropylbenzeneethanamine

hydrochloride) . Matsumoto 2004 identifies the following Sig-IR selective antagonists: NE100 (4-Methoxy-3- (2- phenylethoxy) -N, N-dipropylbenzeneethanamine

hydrochloride), AC927, AZ66, and BD1008 (N-[2-(3,4- dichlorophenyl) ethyl] -N-methyl-2- (1- pyrrolidinyl) ethylamine) . Matsumoto 2001 identifies the following Sig-IR selective antagonists: BD-1047 (N-[2- (3, 4-dichlorophenyl) ethyl] -N-methyl-2- 2 (dimethylamino) ethylamine, BD1060, BD1067, and LR132. Cobos 2008 identifies the following Sig-IR selective antagonists: MS-377 ( (R) - (+) -1- (4-chlorophenyl) -3- [4- (2-methoxyethyl) piperazin-l-yl] methyl-2-pyrrolidinone L- tartrate) , progesterone, and BD1063 (l-[2-(3,4- dichlorophenyl ) ethyl] 4-methylpiperizin) . Other known Sig-IR selective antagonists are BMY-14802 (Paquette 2009), and SlRA (E-52862) (Diaz 2012). Other examples include related analogs of any of the aforementioned antagonists . As used herein, a "Sig-IR antagonist" relates to a selective antagonist of the Sigl-R. The antagonist may be selective in the specific system used, even if antagonizes other receptors in different conditions or system. Matsumoto 2004 identifies the following Sig-IR antagonists: UMB 100, UMB 101, UMB 103, YZ-069, NE100 (4-Methoxy-3- (2-phenylethoxy) -N,N- dipropylbenzeneethanamine hydrochloride), AC927, AZ66, and BD1008 (N- [2- (3, 4-dichlorophenyl) ethyl] -N-methyl-2- ( 1-pyrrolidinyl) ethylamine) . Matsumoto 2001 identifies the following Sig-lR antagonists: BD-1047 (N-[2-(3,4- dichlorophenyl) ethyl] -N-methyl-2-

2 (dimethylamino) ethylamine, BD1060, BD1067, and LR132. Cobos 2008 identifies the following Sig-lR antagonists: haloperidol, reduced haloperidol, Rimcazole (9-{3- [ (3R, 5S) -3, 5-dimethylpiperazin-l-yl] propyl } -9H-carbazo) , Panamesine (EMD 57455), YZ-011, Dup 734, (+)-MR 200, Metaphit, MS-377 ( (R) - (+) -1- ( 4-chlorophenyl ) -3- [4- (2- methoxyethyl) piperazin-l-yl] methyl-2-pyrrolidinone L- tartrate) , progesterone, and BD1063 (l-[2-(3,4- dichlorophenyl) ethyl] 4-methylpiperizin) . Seminerio 2008 identifies the following Sig-lR antagonists: SSR125047, SR31742, and AC927. Other known Sig-lR antagonists are BMY-14802 (Paquette 2009), S1RA (E-52862) (Diaz 2012), ΔΖ66 (Seminerio 2013), CM156 (Xu 2010), E-5842 (4-[4- fluorophenyl] -1,2,3, 6-tetrahydro-l- [4- { 1, 2, 4-triazol-l- il }butyl] pyridine citrate) (Guitart 2006), LR172 (McCracken 1990), UMB 116 (Daniels 2006), and YZ-185 (Sage 2013) . Other examples include related analogs of any of the aforementioned antagonists.

"Conditions which induce apoptosis" as used herein are culture conditions that increase the number of cells undergoing apoptosis. Such conditions include but are not limited to conferring different kinds of stress on the cells, exemplified by culturing in serum-free medium and oxidative stress, culturing the cells with apoptosis inducing factors, activation of apoptotic signals and more . Examples of neurodegenerative diseases or neurodegenerative disorders related to Sig-lR include but are not limited to: neuropsychiatric diseases, methamphetamine addiction, Huntington's disease, cocaine addiction, alcohol addiction, amnesia, pain, neuropathic pain depression, mood disorder, major depressive disorder, psychotic (or delusional) major depression, Alzheimer's disease, stroke, retinal neuroprotection, HIV infection, Schizophrenia, cancer, Parkinson's disease, parkinsonian, anxiety disorders, obsessive- compulsive disorder, Pseudobulbar effect, familial adult or juvenile amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) age-related cognitive impairments, juvenile amyotrophic lateral sclerosis (ALS), glaucoma (Maurice 2009, Francardo 2014, Ishikawa 2009, Kourrichl 2012).

It had been shown that an agonist-antagonist relationship regarding sigma-1 receptors exists in models of methamphetamine and cocaine addiction, amnesia, pain, depression, Alzheimer's disease, stroke, retinal neuroprotection, HIV infection, and cancer. (Maurice 2009) . Sigma-1 receptors have also been implicated in higher-ordered brain functions and play important roles in the pathophysiology of neuropsychiatric diseases such as schizophrenia, depression, anxiety disorders, and dementia (Ishikawa 2009) . Additionally, pharmacological modulation of the sigma-1 receptor produces functional neurorestoration in experimental parkinsonism (Francardo 2014).

It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, "20-40 mg" includes 20.0 mg, 20.1 mg, 20.2 mg, 20.3 mg, etc. up to 40.0 mg. Pharmaceutically Acceptable Salts

The active compounds for use according to the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the compound of the invention.

Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate , and the like. Such salts may be formed by procedures well known and described in the art.

Pharmaceutical Compositions

While the compounds for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredients, optionally in the form of physiologically acceptable salts, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries .

In an embodiment, the invention provides pharmaceutical compositions comprising the active compounds or pharmaceutically acceptable salts or derivatives thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic ingredients know and used in the art. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof . The pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy. Preferred routes of administration include oral administration, in particular in tablet, in capsule, in drage, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical composition of the invention can be manufactured by the skilled person by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.

Further details on techniques for formulation and administration may be found in the latest edition of Remington'^' s Pharmaceutical Sciences (Maack Publishing Co. , Easton, PA) .

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Experimental Details

Examples

Examples 1-5

Huntington's Disease

Huntington disease (HD) is a neurodegenerative, dominantly transmitted disease whose single HTT gene mutation results in the synthesis of mutant huntingtin (mHtt) protein. The resulting mutant protein causes a cascade of toxic events in the nervous system leading to neuronal cell death, and a progressively disabling phenotype including hyperkinetic and hypokinetic clinical abnormalities in HD patients. Pridopidine

Pridopidine' s (ACR16, TV-7820, Huntexil) chemical name is 4- (3- (Methylsulfonyl) phenyl) -1-propylpiperidine, and its Chemical Registry number is 882737-42-0 (U.S. Publication No. US-2013-0267552-A1) . Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459. U.S. Patent No. 6,903,120 claims pridopidine for the treatment of Parkinson's disease, dyskinesias, dystonias, Tourette's disease, iatrogenic and non- iatrogenic psychoses and hallucinoses , mood and anxiety disorders, sleep disorder, autism spectrum disorder, ADHD, Huntington's disease, age-related cognitive impairment, and disorders related to alcohol abuse and narcotic substance abuse.

Pridopidine is a dopamine stabilizer which modulates dopamine transmission and regulates both hyper- and hypoactive motor functioning depending on the prevailing dopaminergic tone. It is currently in development for the symptomatic treatment of Huntington Disease and the neuroprotective potential of the drug is unknown. Some of the pharmacological effects of dopamine stabilizers on dopamine transmission could be neurotrophic and neuroprotective for neuronal cells as they interact with a number of pathways involved in cell survival and proliferation. Although pridopidine binds to striatal dopamine D2 receptor both in vivo and in vitro, its functional effects are not confined to alterations originating from the dopamine pathway.

In patients with HD, the guiding hypothesis is that presynaptic activation of the nigrostriatal dopamine (DA) pathway induces chorea while loss of DA inputs induces bradykinesia (Bird 1980, Spokes 1980) , thus giving rise to the biphasic motor symptoms of early and late HD; hence either abnormally reinforcing or reducing dopaminergic effects may worsen the symptoms severity and disease progression.

Although the dopaminergic circuitry in HD is thought to be complex, current opinions support its relevance as therapeutic target and give rise to the hypothesis that DA stabilizers may provide new valuable treatment options.

Pridopidine has been previously tested in patients with Parkinson's disease (Tedroff 2004), schizophrenia (Carlsson 2006) and is currently in development for the symptomatic treatment of HD. Recent clinical studies identified pridopidine as a molecule with promising therapeutic potential for patients with HD (de Yebenes 2011, Squitieri 2013, Huntington Study Group HART Investigators 2013) . In two double-blind, randomized phase II (HART study) and phase III (MermaiHD study) clinical trials, pridopidine has been shown to improve overall motor function, as measured by the Unified Huntington's disease Rating Scale (UHDRS) Total Motor Score (de Yebenes 2011, Huntington Study Group HART Investigators 2013) and to display a favourable safety and tolerability profile in patients with HD, even after one year treatment (Squitieri 2013) . Although the favourable profile, the intriguing abilities to modulate dopamine-related behaviour and the long-term effects pridopidine has shown in HD patients are encouraging, the exact mechanism by which these effects are induced is not fully understood and the neuroprotective potential of the drug is unknown. Some of the pharmacological effects of dopamine stabilizers on dopamine transmission could be neurotrophic and neuroprotective for neuronal cells as they interact with a number of pathways involved in cell survival and proliferation (Ruiz 2012). Although pridopidine binds to striatal dopamine D2 receptor both in vivo (Natesan 2006) and in vitro (Tadori 2007), its functional effects are not confined to alterations originating from the dopamine pathway (Ponten 2010, Nilsson 2004) .

The Sig-lR is a two-transmembrane domain protein, widely distributed in different regions of the central nervous system (CNS) , with involvement in memory, emotion, sensory and motor function tasks (Hellewell 1994, Novakova 1995) . Sig-lR is a novel molecular chaperone regulating protein folding and degradation at the endoplasmic reticulum (ER) (Hayashi 2007). Its selective agonism may ameliorate the accumulation of misfolded proteins in the CNS (Hayashi 2011) and increase cell survival in a HD cell model (Hyrskyluoto 2013) . The Sig-IR is described in the following publications which are incorporated into this application by reference: Francardo 2014, Maurice 2009, Ruscher 2011, Miki 2014, Hayashi 2007, Vagnerova 2006, and Ishikawa 2010

The potential neuroprotective effect of pridopidine in pre-clinical HD models was explored. This provided evidence that supports a potential disease-modifying action of the drug and clarification other aspects of pridopidine mode-of-action.

Methods of Examples 1-5

Chemicals. Pridopidine was provided by Neurosearch (NEUR: Copenhagen) . NE100 was purchased from Santa Cruz and dissolved according to the manufacturer' s instructions.

Animal models. All in vivo experiments were conducted in R6/2 transgenic mice expressing exon 1 of human Htt with approximately 160 +/- 10 (CAG) repeats and WT littermates maintained on the B6CBA strain (Jackson Laboratories; Bar Harbor, Maine, USA) . Animals were housed singly and maintained under a 12-h light/dark cycle environment in a clean facility and given free access to food pellets and water. Experimenters were blind to either the genotype of the mice or to the treatment. A total of 60 R6/2 mice and 50 WT littermates were used in this study. Mice from the same F generation were assigned to experimental groups, such that age and weight were balanced. Biochemical and histological experiments were carried out on mice brain tissues, euthanized at fixed time points. R6/2 mice used for testing the effect of pridopidine on animal lifespan died naturally. All experiments were performed in accordance with the national requirements for animal research and with the approval of the animal care committee at IRCCS Neuromed. In-vivo drug administration. Pridopidine was dissolved in saline (vehicle) and daily administered by intraperitoneal (i.p.) injection at dose of 5mg/kg or 6mg/kg of body weight. Control mice (WT and R6/2) were daily injected with the same volume of vehicle.

Motor behavior tests and survival study. Training and baseline testing for motor function were carried out prior of pridopidine administration. General motor function was measured once a week during the entire period of the treatment. Locomotor behavior and motor performance were performed using the open field and the horizontal ladder task, respectively, as previously described (Di Pardo 2012) . Spontaneous locomotion and general motor activity were analyzed in the open field. Mice was placed in the centre of a square arena and allowed to explore it for 5 min. Quantitative analyses were performed on the total distance travelled. The arena was cleaned with 10% ethanol between each animal. Skilled walking, limb placement and limb coordination were all assessed by the ladder rung walking task. Mice were placed upon a horizontal ladder and the number of times the animal missteps its paw through the ladder was counted. All tests took place during the light phase of the light- dark cycle and all tests were carried out blindly to the treatment. All mouse cages were daily examined in order to determine lifespan. Brain pathology and Immunohistochemistry . WT and R6/2 mice were sacrificed by cervical dislocation, brains were surgically removed from the skull and trimmed by removing the olfactory bulbs and spinal cord. The remaining brain was then weighed in mg, processed and embedded in paraffin wax and 10 μπι coronal sections were cut on an RM 2245 microtome (Leica Microsystems) . Five mice/group (n = 5) were used and four coronal sections spread over the anterior-posterior extent of the brain

(100-200 μνα inter-section distance) were scanned. For each coronal section, a total number of 10 fields at 63x magnification were analyzed. Immunostaining for mutant Htt aggregates was carried out using EM48 antibody

(1:100) (Millipore) (Li 2001). Htt inclusions were defined as EM48-positive staining at the light microscope level. The average area of striatal mHtt aggregates per brain section was quantified by ImageJ software . Protein lysate preparation . Analysis of variation of protein expression after pridopidine administration was performed by biochemical assays on brain regions. Dissected brain tissues were snap frozen in liquid N2 and pulverized in a mortar with a pestle. Pulverized tissue was homogenized in lysis buffer containing 20 mM Tris, pH 7.4, 1% Nonidet P-40, 1 mM EDTA, 20 mM NaF, 2 mM Na3V04, and 1:1000 protease inhibitor mixture (Sigma- Aldrich) , sonicated with 2 ^χ 10 s pulses and then centrifuged for 10 min at 10,000 ^x g.

Cell models. Conditionally immortalized mouse striatal knock-in cells expressing endogenous levels of wild-type (STHdh^7/7) or mHtt (STHdh^111/lu) were purchased from the Coriell Cell Repositories (Coriell Institute for Medical Research, Camden, NJ) and were maintained as previously- described (Maglione 2010) .

Analysis of apoptosis . Different concentrations of pridopidine (100, 150, 200 and 300 μΜ) were tested to investigate the anti-apoptotic effect of the molecule on immortalized cells cultured in serum-free medium at 39°C for six hours. In NE100 experiments, cells were pre- incubated with the compound (10 μΜ) for two hours before culturing them in apoptotic conditions. At the end of each treatment, cells were collected and incubated with FITC-conjugated Annexin V (Southern Biotech) according to the manufacturer's instructions. FACS analysis was performed as previously described in Maglione 2010.

Lysates preparation . Cells were cultured for 5 hours at 33°C in serum-free medium then treated with 150 μΜ pridopidine for 10 min and lysate in lysis buffer containing 20 mM Tris, pH 7.4, 1% Nonidet P-40, 1 mM EDTA, 20 mM NaF, 2 mM Na3V04, and 1:1000 protease inhibitor mixture (Sigma-Aldrich) , sonicated with 2 χ 10 s pulses and then centrifuged for 10 min at 10,000 * g. In NE100 experiments, cells were pre-incubated with the compound for two hours before adding pridopidine.

Immunoblottings . 40 g of total protein lysate were resolved on SDS-PAGE and immunoblotted with specific antibodies. Anti-phospho-ERK (1:1000) and anti-ERK (1:1000) (all from Cell Signaling) were used for analysis of the kinase activation. For the analysis of DARPP-32, BDNF expression total lysate were immunoblotted with the anti-DARPP-32 (1:1000) (Cell Signaling), anti-BDNF (1:500) (Santa Cruz) respectively. Mutant huntingtin aggregates were detected using EM48 antibody (1:1000) (Millipore) . Anti-aTubulin (1:5000) (Abeam) or anti-pActin (1:3000) (Sigma) antibodies were used for protein normalization. HRP-conj ugated secondary antibodies (GE-Healthcare) were used at 1:5000 dilution. Protein bands were detected by ECL Prime (GE Healthcare) and quantitated with Quantity One (Bio-Rad Laboratories) and/or ImageJ software.

Statistics. Two-way ANOVA followed by Bonferroni post- test for multiple comparisons was used to compare treatment groups in the open field and horizontal ladder tests. Kaplan Meier curves employing Log-Rank Test were used to analyze mice survival. Non-parametric Mann Whitney U was used to analyze cell survival, mouse brain weight, BDNF, DARPP-32 protein levels. Two-tailed t-test was employed in all other experiments. All data are expressed as mean ± SD.

Results of Examples 1-5

Example 1 Results: Pridopidine improves motor function and prolongs life-span in pre-symptomatic HD mice.

To further confirm the beneficial effect of pridopidine on HD motor phenotype and to elucidate whether the molecule may act also as neuroprotective agent, preclinical studies in R6/2 mice was undertaken. Daily administration of pridopidine (5mg/kg) , the most effective dose with no adverse effects (data not shown) , starting at the pre-symptomatic stage, significantly preserved motor function and prevented the progressive and dramatic motor worsening commonly observed in R6/2 mice (Figure 1A, IB) . The results indicate that the beneficial effects of the drug were maintained for about 4 weeks, after which mice showed a slight worsening in performing both the horizontal ladder task and the open field (Figure 1A, IB) . In addition, according to the Kaplan-Meier survival curve, pridopidine efficiently extended lifespan in the same mice (Figure 1C) , suggesting a neuroprotective potential of the drug.

Example 2 Results: Pridopidine transiently improves motor function in symptomatic HD mice .

In order to investigate whether the administration of pridopidine could exert similar beneficial effect or restore normal motor function in the advanced HD stage, symptomatic R6/2 mice with evident compromised motor function were chronically treated with pridopidine or placebo starting at 7 weeks of age. After a marked improvement in motor symptoms within the first week of treatment, mice appear to become less responsive to the drug, and disease severity increases to be almost indistinguishable from symptomatic vehicle-treated mice ( Figure 2) . In this regard, we tested the possibility that an increased dose of pridopidine (6 mg/kg) , which resulted to cause hypokinesia if administered at the beginning of the treatment (data not shown) , could re-establish the effectiveness of the drug on motor performance. One week of the higher dose of pridopidine blocked the progression of motor decline and triggered the recovery of motor function in symptomatic R6/2 mice (Figure 2).

Example 3 Results : Pridopidine positively modulates the expression of neuroprotective molecules in R6/2 mice.

To explore whether molecular targets (i.e. BDNF and DARPP32), normally involved in the control of brain function and homeostasis and, commonly associated with neuroprotection, varied with pridopidine treatment, biochemical analysis were carried out in both pre- symptomatic and symptomatic R6/2 mice. After chronic administration of 5mg/kg of pridopidine we did not detect any difference in the expression of BDNF between pridopidine-treated and vehicle-treated mice in striatal or in cortical tissues (Figure 6A, 6B) . On the other hand, immunoblotting analysis of DARPP32 highlighted a slight increase of protein expression in pridopidine- treated R6/2 mice (Figure 6C) . Although not statistically significant, the tendency toward increased DARPP32 expression is suggestive of a potential neuroprotective action of the drug. To further investigate the neuroprotective properties of pridopidine, we increased the dose of pridopidine (from 5 to 6mg/kg) and observed, after one week of treatment, a restoration of normal expression of both BDNF and DARPP32 protein in the striatal lysate from treated R6/2 mice (Figure 3A, 3B) . No changes of BNDF levels were detected in lysate from cortical tissues (Figure 7).

Example 4 Results: Pridopidine significantly reduces the size of mHtt aggregates in the striatum of R6/2 mice.

To elucidate whether pridopidine could have any effect on mHtt toxicity and aggregates formation in the brain, at the end of the treatment R6/2 mice were sacrificed and immunodetection of mutant protein aggregation in the striatal tissues was performed. Immunostaining analysis of EM48 positive cells revealed a significant reduction in the size of single aggregates in pridopidine-treated R6/2 compared with vehicle-infused mice (Figure 4A, 4B) . The ability of pridopidine to reduce mHtt aggregates was also confirmed by immunoblotting analysis (Figure 4C) . Next, in order to elucidate the widespread effects that pridopidine could have on the brain anatomy changes in the brain weight as an index of global disruption of neuronal systems, a common feature of HD, was investigated. It was found that brains from vehicle- treated R6/2 mice weighted around 15% less than brains from wild-type (WT) littermates (Figure 8) . Mice chronically treated with pridopidine displayed a slight trend toward the preservation of brain weight loss, however it did not reach any statistically significant difference compared with vehicle-treated mice (Figure 8) .

Example 5 Results : The neuroprotective and the anti- apoptotic effect of pridopidine is mediated by Sig-IR in HD cell model .

To clarify the neuroprotective efficacy of pridopidine and to explore the potential underling molecular mechanism, the ability of pridopidine to protect cells from apoptosis and to eventually activate pro-survival targets was evaluated. Administration of pridopidine (150 μΜ) , the most effective dose (Figure 9) , significantly reduced apoptosis in immortalized striatal knock-in cells expressing endogenous levels of mutant Htt (STHdh^111/111) (Figure 5A) and markedly enhanced phosphorylation state of prosurvival kinase ERK (Figure 5B) . The neuroprotective effect of pridopidine and its ability to promote activation of pro-survival pathways in vitro was completely abolished in presence of NE100, a selective antagonist of Sig-IR, suggesting this latter to play a key role in determining the effectiveness of the drug in HD cells (Figure 5A, 5B) . Moreover, the specific antagonist of Sig-IR partially prevented pridopidine-induced reduction of mHtt aggregates in HD cells (Figure 5C) .

Discussion of Examples 1-5:

Dopamine (DA) imbalance plays a key role in the pathophysiology of a number of neuropsychiatric and neurodegenerative diseases (Beaulieu 2011), including HD (Andre 2010) . Dopamine alterations have been reported in mouse models of HD (Mochel 2011, Crook 2012) and post- mortem tissues from HD patients (Huot 2007, Jahanshahi 2013) and may account for both motor and non-motor manifestations of the disease. There is evidence of a progressive reduction of striatal DA levels concomitant with motor abnormalities in both systems.

Dopaminergic input is crucial for the regulation of corticostriatal synaptic transmission and since the abnormalities in the DA system appear to underlie many of the behavioral symptoms of HD, treatment with modulators of dopaminergic neurotransmission may have therapeutic value for the disease. Current treatment options for HD are confined to anti-dopaminergic agents, often accompanied with serious side effects (Armstrong 2012, Reilmann 2013) . However, promising research on the development of dopamine-stabilizer molecules, offers new hope. Pridopidine, a dopamine stabilizer, is currently under evaluation in the "HD-Pride" trial, for symptomatic treatment of HD, after the compound completed a previous Phase III clinical study in Europe (MermaiHD study) and a Phase II study in the US (HART study) (de Yebenes 2011, Squitieri 2013). The two studies failed to find statistically significant effects in the primary endpoint of modified motor score (mMS) but found positive effects on the secondary endpoint of the total motor score (TMS) of the UHDRS (Waters 2010) . Patients receiving pridopidine displayed these improvements in their motor symptoms without deleterious side effects (Squitieri 2013). The discovery of such beneficial effect of pridopidine on motor function supports the molecule as potential novel therapy and corroborates the hypothesis that pridopidine may have disease-modifying properties in HD.

Pridopidine is unique because depending on the levels of dopamine in the cells, it will either have stimulatory or inhibitory effects (Lundin 2010). It is, however, challenging to determine whether the clinical benefits of pridopidine are due to short-term symptomatic effects or to the potential neuroprotective long-term properties of the drug.

Preclinical studies for both in vivo and in vitro models of HD have been undertaken. Treatment with pridopidine significantly improved the overall neurological phenotype in R6/2 mouse model and the therapeutic benefits, seen across outcome measures, included improvement of motor performance, extension of survival and neuroprotection. Intriguingly, in this study a link between pridopidine dose and beneficial effects in R6/2 mice was observed. The initial dose of pridopidine (5mg/kg) , after the first few weeks of therapeutic efficacy, became less effective and an increased dose of the pridopidine (6mg/kg) was needed for it to keep being efficacious.

The optimal dose of pridopidine was established in a pilot study, during which different doses of the drug (2.5, 5, 6 and 10 mg/kg) were daily administered. When given at high doses (10 mg/kg) , pridopidine induced remarkable side effects such as rigidity and akinesia (data not shown) . Dose of 5mg/kg pridopidine, instead, was found to be the most effective one with no adverse effects. Even though it is only slightly higher than the most effective dose, 6mg/kg pridopidine was deleterious to some aspects of motor performance when administered as starting dose (data not shown) ; these observations suggest that the choice of dosage is critical and further studies may be useful to clarify whether the need of varying pridopidine dose possibly reflects the dynamic and time-dependent changes that occur in the DA system as the disease progresses.

Besides confirming the potential of pridopidine to represent a symptomatic treatment in HD, the findings highlight a neuroprotective action of the drug; administration of pridopidine increased the expression of both BDNF and DARPP32 protein, normally implicated in neuronal health (Binder 2004, Reis 2007) and ameliorated mHtt aggregation, commonly linked to mHtt toxicity (Sanchez 2003) . Pridopidine protected HD cells from apoptosis and promoted the activation of pro-survival kinase ERK.

From mechanistic standpoint, the data implies that Sig- 1R is part of the mechanism of action of pridopidine and indicates that the anti-apoptotic effect of drug in vitro may depend on the stimulation of such receptor. In support of that, it was demonstrated that pharmacological blockage of Sig-IR, by a selective antagonist NE100, completely abolished cell survival and ERK activation mediated by pridopidine, in vitro. Based on these observations, and for a better understanding of neuroprotective action of pridopidine, other targets beside dopamine receptors should be considered. The involvement of Sig-IR may help to clarify the putative mechanisms of action through which the dopamine stabilizer exerts its therapeutic action. Example 6: Drug compensation of ER stress in cellular models of Huntington's disease. Evaluation of early Endoplasmic Reticulum (ER) stress by expression of H2aGFP and Htt-cherry (exon 1, 96Q vs. control 20Q) in STHd ^Q7/7 cells and compensation by drug. Measurement of drug effects on Htt-cherry aggregation.

Aggregation of Htt 96Q-cherry inhibits Endoplasmic reticulum-associated protein degradation (ERAD) and induces ER stress, causing an accumulation of H2aGFP (ERAD substrate) in the ERQC (Leitman 2013) (Figure 10A) . Incubation of cells with pridopidine reduced this accumulation (Figure 10B) .

The intensity of H2aGFP in many single cells showing Htt96Q-cherry was quantified. The effect of the four previously established pridopidine concentrations was evaluated. Figure IOC presents the quantitative results of 3 experiments, with quantitation of about 150 cells expressing H2aGFP and Htt96Q-cherry in each experiment. The graph shows the average percent of ER stress relative to untreated cells +-SD. The ER stress scale is set as 0% for untreated cells expressing Htt96Q-cherry that do not present aggregates and 100% for untreated cells with Htt 96Q-cherry aggregates. Pridopidine caused a significant concentration dependent reduction of ER stress. There is a larger variability between experiments at the highest concentration of pridopidine (50 pg/ml) , is likely because this concentration causes by itself some stress. Figure 10D is a control that shows quantitative results of 3 experiments, with quantitation of about 150 cells expressing H2aGFP and Htt20Q-cherry in each. As Htt20Q- cherry does not aggregate, cells expressing H2aGFP and Htt 6Q-cherry were used in parallel to establish the 100% mark in the ER stress scale and be able then to compare with the results of Figure IOC. As can be seen, in this control experiment the concentration effect of pridopidine is negligible, except for a small (and not significant) increase in ER stress at the highest concentration of pridopidine (50 pg/ml) . This suggests that pridopidine causes no ER stress by itself, except at concentrations higher than 50 μg/ml.

The number of cells presenting Htt96Qcherry aggregates was counted and it was calculated what percent of the total number of cells expressing Htt96Q-cherry this represented. We then evaluated the effect of pridopidine on the percent of cells with aggregates. Pridopidine caused no significant change in the levels of aggregates ( Figure 11 ) .

Example 6 Conclusions

These experiments suggest that pridopidine reduces ER stress caused by pathogenic huntingtin in a dose- dependent manner. The effect is present in the whole range tested, from 0.01 to 50 pg/ml. There is no ER stress caused by these concentrations of pridopidine except for a small effect at the highest concentration (50 μg/ml) . Pridopidine does not seem to reduce ER stress by direct inhibition of Htt96Q aggregation but by affecting some downstream factor. Example 7 : Drug compensation of ER stress in cellular models of Huntington's disease. Evaluation of Sigma-1 receptor (Sigma-lR) behavior. Sigma-IR-GFP intensity levels and subcellular location in the presence of Htt- cherry (exon 1, 20Q vs. 96Q) in STfidh^Q7/7 cells and the effect of pridopidine .

Sigma-lR is a suspected target of pridopidine and its subcellular relocation during ER stress was demonstrated. The effect of tt96Qcherry expression on Sigma-IR-GFP was first analyzed. Similar to the effect that we had seen of drug induced UPR, Htt96Q-cherry caused a dramatic change in the pattern of Sigma-IR-GFP, from disperse and vesicular to perinuclear patches (Figure 12) . The levels of Sigma-IR-GFP per cell increased significantly in the presence of Htt96Q-cherry (Figure 13A) . Incubation with pridopidine caused a further, concentration-dependent increase in Sigma-IR- GFP levels, which was significant at 50 g/rαl· (Figure 13B) . There was no significant change in Sigma-IR-GFP pattern or levels upon expression of control Htt20Q- cherry (Figure 12) and no effect of pridopidine (Fig. 13C) . Example 7 Conclusions:

These results suggest that pridopidine stabilizes Sigma- IR-GFP steady state levels in the presence of Htt96Q- cherry. As there was no effect of pridopidine on Sigma- IR-GFP levels in the presence of Htt20Q-cherry, the effect is dependent on the changes caused by Htt96Q- cherry aggregation. One possible explanation is that the degradation of Sigma-IR-GFP is inhibited in the presence of Htt96Q-cherry and is further inhibited by the action of pridopidine. The lack of effect of pridopidine in the absence of Htt96Q-cherry would imply that Htt96Q inhibits the main degradation pathway of Sigma-IR-GFP and induces a less efficient alternative pathway, which is sensitive to pridopidine. Although its molecular functions are still unclear, Sigma-lR is localized in the ER and was reported to have cytoprotective chaperone activities and to be involved in ERAD (Mori 2013) . Sigma-lR has also been shown to accumulate in neurodegenerative diseases (Miki 2014). Its stabilization would be protective to cells stressed by Htt 96Q-cherry aggregation.

Example 8 : The neuroprotective and anti-apoptotic effect of SA4503 (Cutamesine) in HD cell model is mediated by Sig-IR

A. Conditionally immortalized mouse striatal knock-in cells expressing endogenous levels of wild-type (STHdh^7/7) or mHtt (STHdh¹¹¹/¹¹¹) are cultured in serum- free medium at 39°C for six hours in the present of SA4503. In NE100 experiments, cells are pre-incubated with NE100 (10 μΜ) for two hours before culturing them in apoptotic conditions. At the end of each treatment, cells are collected and incubated with FITC-conj ugated Annexin V according to the manufacturer's instructions. FACS analysis is performed as previously described.

Administration of SA4503 significantly reduces apoptosis in immortalized striatal knock-in cells expressing endogenous levels of mutant Htt (STHdh^111/111) . The antiapoptotic effect of SA4503 is inhibited in the presence of NE100, a selective antagonist of Sig-IR.

B. Conditionally immortalized mouse striatal knock-in cells expressing endogenous levels of wild-type (STHdh^7/7) or mHtt (STHdh^111/ul) are cultured in serum- free medium at 39°C for six hours in the present of SA4503. In NE100 experiments, cells are pre-incubated with NE100 (10 μΜ) for two hours before culturing them in apoptotic conditions. At the end of each treatment, cells are collected and incubated with FITC-conj ugated Annexin V according to the manufacturer's instructions. FACS analysis is performed as previously described.

Administration of SA4503 markedly enhances phosphorylation state of prosurvival kinase ERK in immortalized striatal knock-in cells expressing endogenous levels of mutant Htt (STHdhⁱⁿ/ui ) . _The ability of SA4503 to promote activation of pro-survival pathways is inhibited in the presence of NE100, a selective antagonist of Sig-IR.

Example 9 : The neuroprotective and anti-apoptotic effect of agonists of the Sigma-1 receptor in HD cell model is mediated by Sig-IR.

(+) -pentazocine) , (-) -Pentazocine, (+)-SKF 10047, clorgyline, Fluoxetine, Fluvoxamine, imipramine, Carbetapentane, Dextromethorphan, Dextrorphan,

Dimemorfan, amantadine, donepezil, memantine, neurosteroid dehydroepiandrosterone-sulfate (DHEA-S) , Pregnenolone sulfate, BD 737, 4-IBP, (+) -Igmesine, OPC- 14523, (+) -3- (3-Hydroxyphenyl) -N- (1-propyl) -piperidine, PRE-084, (±)-PPCC oxalate, ANAVEX 2-73, DMT (N,N- Dimethyltryptamine) , ANAVEX 1-41, DHEA BD1031, BD1052, Pentoxyverine, UMB23, UMB41, UMB82, Ditolylguanidine, 4-phenyl-l- ( 4-phenylbutyl) piperidine) , opipramol and ANAVEX 3-71 are each tested individually as described in Example 8. The results for each are similar to those described Example 8. References Cited:

Andre VM, Cepeda C, Levine MS (2010) Dopamine and glutamate in Huntington's disease: A balancing act. CNS Neurosci Ther 3: 163-78. Armstrong MJ, Miyasaki JM. (2012) Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 6: 597-603. Beaulieu JM, Gainetdinov RR. (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 1: 182-217.

Binder DK, and Scharfman HE. (2004) Brain-derived neurotrophic factor. Growth Factors 22: 123-131. Bird ED (1980) Chemical pathology of Huntington's disease. Annu Rev Pharmacol Toxicol 20: 533-51.

Botana, Luis M. and Loza, Mabel, Therapeutic Targets: Modulation, Inhibition, and Activation (2012).

Carlsson A, Carlsson ML (2006) A dopaminergic deficit hypothesis of schizophrenia: the path to discovery. Dialogues Clin Neurosci. 137-142.

Chen JY, Wang EA, Cepeda C, Levine MS (2013) Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility. Front Neurosci 4(7): 114.

Chou, Yueh-Ching et al. Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan. Brain Research, Volume 821, Issue 2, 13 March 1999, Pages 516-519.

Cobos, E.J et al., Pharmacology and Therapeutic Potential of Sigmal Receptor Ligands. Curr Neuropharmacol. Dec 2008; 6{4): 344-366

Crook ZR, Housman DE . (2012) Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice. Proc Natl Acad Sci U S A 19: 7487-92. Cuevas J, Rodriguez A, Behensky A, Katnik C. Afobazole modulates microglial function via activation of both sigma-1 and sigma-2 receptors. J Pharmacol Exp Ther. 2011 Oct;339 (1) :161-72.

Daniels, Ayala E, Chen W, Coop A, Matsumoto RR, N-[2-(m- methoxyphenyl) ethyl] -N-ethyl-2- (1- pyrrolidinyl) ethylamine (CJMB 116] is a novel antagonist for cocaine-induced effects. Eur J Pharmacol. 2006 Aug 7;542 (1-3) : 61-8. de Yebenes JG, Landwehrmeyer B, Squitieri F, Reilmann R, Rosser A, et al. (2011) Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD) : a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol 12: 1049-57.

Dhir Al, Kulkarni SK. Possible involvement of sigma-1 receptors in the anti-immobility action of bupropion, a dopamine reuptake inhibitor. Fundam Clin Pharmacol. 2008 Aug;22 (4) :387-94.

Diaz JL1, at al. Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4- { 2- [5-methyl-l- (naphthalen-2-yl) -1H- pyrazol-3-yloxy] ethyl }morpholine (S1RA, E-52862). J Med Chem. 2012 55 (19) :8211-24.

Di Pardo A, Maglione V, Alpaugh M, Horkey M, Atwal RS, et al. (2012) Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci U S A. 9: 3528-33.

Ishima et al., Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharmacol. 2014 Mar 15/727:167-73.

Francardo et al . , Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental Parkinsonism. Brain (2014). Hayashi T, Su TP. (2005) Understanding the Role of Sigma-1 Receptors in Psychotic Depression,

Pathophysiology.

Hayashi T, Su TP. (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 3: 596-610.

Hayashi T, Tsai SY, Mori T, Fujimoto M, Su TP. (2011) Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatrxc disorders. Expert Opin Ther Targets. 5: 557-77. Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, et al. (1994) Rat liver and kidney contain high densities of sigma 1 and sigma 2 receptors: characterization by ligand binding and photoaffinity labeling. Eur J Pharmacol 1: 9-18. Hajipour et al . , The hallucinogen N, N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science 323, 934 (2009) .

Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotid repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971983.

Huntington Study Group HART Investigators (2013) A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington's disease. Mov Disord 10: 1407-15.

Huot P, Levesque M, Parent A. (2007) The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea. Brain 130: 222-32. Hyrskyluoto A, Pulli I, Tornqvist K, Ho TH, Korhonen L, et al. (2013) Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the N F- KB pathway. Cell Death Dis 23(4): e646. Guitart X. et al., E-5842: A New Potent and Preferential Sigma Ligand. Preclinical Pharmacological Profile, (2006) CNS Drug Reviews, Vol. 4, No. 3, pp. 201-224.

Jahanshahi A, Vlamings R, van Roon-Mom WM, Faull RL, Waldvogel HJ, et al. (2013) Changes in brainstem serotonergic and dopaminergic cell populations in experimental and clinical Huntington's disease. Neuroscience 15; 238: 71-81.

Katnik et al., Sigma-1 Receptor Activation Prevents Intracellular Calcium Dysregulation in Cortical Neurons during in Vitro Ischemia. JPET 319:1355-1365, 2006 Kirkwood, Sandra Close (2001) Progression of Symptoms in the Early and Middle Stages of Huntington Disease. Arch Neurol. 58 (2) :273-278.

Kobayashi Enhancement of Acetylcholine Release by SA4503, a Novel Sigma-1 Receptor Agonist, in the Rat Brain. JPET 279:106-113, 1996

Kourrich, et al. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends in Neurosciences , December 2012, Vol. 35, No. 12. Kotagale NR, Mendhi SM, Aglawe MM, Umekar MJ, Taksande BG. Evidences for the involvement of sigma receptors in antidepressant like effect of quetiapine in mice. Eur J Pharmacol. 2013 Feb 28 ; 702 ( 1-3 ): 180-6.

Leitman J, Ulrich Hartl F, Lederkremer GZ (2013) Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nat Commun 4: 2753.

Li H, Li SH, Yu ZX, Shelbourne P, and Li XJ. (2001) Huntingtin aggregate associated axonal degeneration is an early pathological event in Huntington's disease mice. J Neurosci 21: 8473-8481.

Robert R. Luedtke et al. Neuroprotective effects of high affinity sigma 1 receptor selective compounds. Brain Res. 2012 Mar 2; 1441: 17-26. Lundin A, Dietrichs E, Haghighi S, Goller ML, Heiberg A, et al. (2010) Efficacy and safety of the dopaminergic stabilizer Pridopidine (ACR16) in patients with Huntington's disease. Clin Neuropharmacol 5: 260-4. Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, et al. (2010) Impaired ganglioside metabolism in Huntington's disease and neuroprotective role of GMl . J Neurosci 11: 4072-80. Masatomo Ishikawa and Kenji Hashimoto, The role of sigma-1 receptors in the pathophysiology of neuropsychiatric diseases. Journal of Receptor, Ligand and Channel Research 2010:3 25-36. atsumoto RR, Gilmore DL, Pouw B, Bowen WD, Williams W, Kausar A, Coop A (May 2004). "Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-induced toxicity in mice". European Journal of Pharmacology 492 (1) : 21-6.

Matsumoto RR et al., "Structure-activity comparison of YZ-069, a novel σ ligand, and four analogs in receptor binding and behavioral studies," Pharmacology Biochemistry and Behavior, vol. 77, no. 4, pp. 775-781, 2004.

Matsumoto RR, McCracken KA, Pouw B, Miller J, Bowen WD, Williams W, De Costa BR (2001). "N-alkyl substituted analogs of the sigma receptor ligand BD1008 and traditional sigma receptor ligands affect cocaine- induced convulsions and lethality in mice". Eur. J. Pharmacol. 411 (3): 261-73. Matsumoto RR et al., Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting σΐ receptors produce anti-cocaine effects in mice. European Journal of Pharmacology, Volume 419, Issues 2-3, 11 May 2001, Pages 163-174 McLarnon J, Sawyer D, Church J. The actions of L- 687,384, a sigma receptor ligand, on NMDA-induced currents in cultured rat hippocampal pyramidal neurons. Neurosci Lett. 1994 Jun 20; 174 (2) : 181- .

McCracken K, Bo en WD, de Costa BR, Matsumoto RR. , Two novel sigma receptor ligands, BD1047 and LR172, attenuate cocaine-induced toxicity and locomotor activity, Eur J Pharmacol. 1999 Apr 16; 370 (3 ): 225-32.

Miki Y, Mori F, Kon T, Tanji K, Toyoshima Y, et al. (2014) Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases. Neuropathology 34: 148-158.

Mochel F, Durant B, Durr A, Schiffmann R. (2011) Altered dopamine and serotonin metabolism in motorically asymptomatic R6/2 mice. PLoS One 3: el8336.

Mori T, Hayashi T, Hayashi E, Su TP (2013) Sigma-1 receptor chaperone at the ERmitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLoS One 8: e76941.

Natesan S, Svensson KA, Reckless GE, Nobrega JN, Barlow KB, et al. (2006) The dopamine stabilizers (S)-(-)-(3- methanesulfonyl-phenyl ) -1-propyl-piperidine [(-)- OSU6162] and 4- ( 3-methanesulfonylphenyl ) -1-propyl- piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat. J Pharmacol Exp Ther 2: 810-8.

Navarro G, Moreno E, Bonaventura J, Brugarolas M, Farre

D, et al. (2013) Cocaine Inhibits Dopamine D2 Receptor

Signaling via Sigma-1-D2 Receptor Heteromers. PLoS ONE 8(4): e61245. Niitsu T. et al . , Sigma-1 receptor agonists as therapeutic drugs for cognitive impairment in neuropsychiatric diseases. Curr Pharm Des.

2012; 18 (7) : 875-83. Nilsson M, Carlsson A, Markinhuhta KR, Sonesson C, Pettersson F, et al. (2004) The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition. Prog Neuropsychopharmacol Biol Psychiatry 4: 677-85.

Novakova M, Ela C, Barg J, Vogel Z, Hasin Y, et al.

(1995) Inotropic action of sigma receptor ligands in isolated cardiac myocytes from adult rats. Eur J Pharmacol 1: 19-30. Paquette MA, Foley K, Brudney EG, Meshul C , Johnson SW, Berger SP (July 2009) . "The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism". Psychopharmacology 204 (4) : 743-54. Ponten H, Kullingsjo J, Lagerkvist S, Martin P, Pettersson F, et al . (2010) In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol 1- 3: 88-95.

Rao TS et al. Neurochemical characterization of dopaminergic effects of opipramol, a potent sigma receptor ligand, in vivo. Neuropharmacology. 1990 Dec;29(12) :1191-7.

Robson MJ, Evaluation of sigma (o) receptors in the antidepressant-like effects of ketamine in vitro and in vivo. Eur Neuropsychopharmacol. 2012 Apr; 22 (4) : 308-17. Reilmann R. (2013) Pharmacological treatment of chorea in Huntington's disease-good clinical practice versus evidence-based guideline. Mov Disord 8: 1030-3.

Reis HJ, Rosa DV, Guimaraes MM, Souza BR, Barros AG, et al. (2007) Is DARPP-32 a potential therapeutic target? Expert Opin T er Targets 12: 1649-61.

Ruiz C, Casarejos MJ, Rubio I, Gines S, Puigdellivol M, et al. (2012) The dopaminergic stabilizer, (-)-OSU6162, rescues striatal neurons with normal and expanded polyglutamine chains in huntingtin protein from exposure to free radicals and mitochondrial toxins. Brain Res 1459: 100-12.

Ruscher et al., The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. Brain (2011).

Sahlholm , Arhem P, Fuxe K, Marcellino D. (2013) The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the σ-l receptor. Mol Psychiatry 1: 12-4. Sage, A. et al., N-Phenylpropyl- ' - ( 3- methoxyphenethyl) iperazine (YZ-185) Attenuates the Conditioned-Rewarding Properties of Cocaine in Mic. ISRN Pharmacology Volume 2013 (2013), Article ID 546314.

Sanchez I, Mahlke C and Yuan J. (2003) Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421: 373-379.

Sari, Youssef (June 2011) Huntington's Disease: From Mutant Huntingtin Protein to Neurotrophic Factor Therapy. Int J Biomed Sci. 7(2): 89-100. Seminerio, Michael J. et al . , The evaluation of AZ66, an optimized sigma receptor antagonist, against methamphetamine-induced dopaminergic neurotoxicity and memory impairment in mice. The International Journal of Neuropsychopharmacology, Volume 16, Issue 05, June 2013, pp 1033-1044.

Seminerio, Michael J. et al., Sigma (σ) receptor ligand, AC927 (N-phenethylpiperidine oxalate) , attenuates methamphetamine-induced hyperthermia and serotonin damage in mice, Pharmacology Biochemistry and Behavior, Volume 98, Issue 1, March 2011, Pages 12-20.

Spokes EG (1980) Neurochemical alterations in Huntington's chorea: a study of post-mortem brain tissue. Brain 1: 179-210. Squitieri F, Landwehrmeyer B, Reilmann R, Rosser A, de Yebenes JG, et al. (2013) One-year safety and tolerability profile of pridopidine in patients with Huntington disease. Neurology 12: 1086-94.

Tadori Y, itagawa H, Forbes RA, McQuade RD, Stark A, et al. (2007) Differences in agonist/antagonist properties at human dopamine D(2) receptors between aripiprazole, bifeprunox and SDZ 208-912. Eur J Pharmacol 2-3: 103-11.

Tangui Maurice and Tsung-Ping Su, The Pharmacology of Sigma-1 Receptors. Pharmacol Ther. 2009 November ; 124 (2) : 195-206.

Tedroff J, Sonesson C, Waters N, Waters ES, Carlsson A (2004) A pilot study of the novel dopamine stabilizer ACR16 in advanced Parkinson's disease Mov Disord 19 p. S201. Vagnerova et al., Sigma 1 receptor agonists act as neuroprotective drugs through inhibition of inducible nitric oxide synthase. Anesth Analg. 2006 Aug;103 (2) :430-4. Wang J et al . , Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice. Eur Neuropsychopharmacol. 2007 Nov; 17 (11) : 708-16.

Waters S , Tedroff J, Kieburtz K. (2010) Validation of the Modified Motor Score (mMS) : a subscale of the Unified Huntington's Disease Rating Scale (UHDRS) motor score. Neurotherapeutics 7: 144.

Xu YT, Kaushal N, Shaikh J, Wilson LL, Mesangeau C, McCurdy CR, Matsumoto RR (2010) . "A novel substituted piperazine, CM156, attenuates the stimulant and toxic effects of cocaine in mice". J. Pharmacol. Exp. Ther. 333 (2) : 491-500.

Chun-Lei Zhang et al., Methylphenidate Enhances NMDA- Receptor Response in Medial Prefrontal Cortex via Sigma- 1 Receptor: A Novel Mechanism for Methylphenidate Action. PLOS ONE, published December 20, 2012

Claims

What is claimed is:

A method of treating a subject suffering from a neurodegenerative disease or neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a modulator of the Sigma-1 receptor so as to thereby treat the subject .

The method of claim 1, wherein the neurodegenerative disease or neurodegenerative disorder is related to the Sigma-1 receptor

The method of claim 1 or 2, wherein the neurodegenerative disease or neurodegenerative disorder is a neurodegenerative disease or neurodegenerative disorder other than Huntington's disease .

The method of any one of claims 1-3 wherein the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of methamphetamine addiction, cocaine addiction, alcohol addiction, pain, mood disorder, major depressive disorder, psychotic or delusional major depression, Alzheimer's disease, HIV infection, Schizophrenia, Parkinson's disease, parkinsonian, anxiety disorders, obsessive-compulsive disorder, stroke, and age-related cognitive impairments.

The method of any one of claims 1-3 wherein the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of neuropsychiatric diseases, amnesia, neuropathic pain depression, retinal neuroprotection,

Pseudobulbar effect, familial adult amyotrophic lateral sclerosis (ALS) , juvenile amyotrophic lateral sclerosis (ALS) , multiple sclerosis (MS) , glaucoma, and cancer.

6. The method of any one of claims 1-5 wherein treating the neurodegenerative disease or neurodegenerative disorder comprises providing neuroprotection in the subject.

7. The method of any one of claims 1-5 wherein treating the neurodegenerative disease or neurodegenerative disorder comprises delaying neurodegeneration in the subject.

8. A method of treating a subject suffering Huntington's disease comprising administering to the subject a therapeutically effective amount of a modulator of the Sigma-1 receptor so as to thereby treat the subject.

9. The method of claim 8, wherein treating the neurodegenerative disease or neurodegenerative disorder comprises delaying neurodegeneration in the subject.

10. The method of claim 8, wherein treating the neurodegenerative disease or neurodegenerative disorder comprises providing neuroprotection in the subj ect .

11. The method of any one of claims 1-10, wherein the modulator is not pridopidine.

12. The method of any of claims 1-11, wherein the modulator of the Sigma-1 receptor is an agonist of the Sigma-1 receptor.

13. The method of any one of claims 1-12, wherein the modulator is at least one member of a group comprising: SA4503 (Cutamesine) , (+) -pentazocine) , (-) -Pentazocine, (+)-SKF 10047, clorgyline,

Fluoxetine, Fluvoxamine, imipramine,

Carbetapentane, Dextromethorphan, Dextrorphan, Dimemorfan, amantadine, donepezil, memantine, neurosteroid dehydroepiandrosterone-sulfate (DHEA- S), Pregnenolone sulfate, BD 737, 4-IBP, (+)- Igmesine, OPC-14523, (+) -3- (3-Hydroxyphenyl) -N- ( 1- propyl) -piperidine, PRE-084, (±) -PPCC oxalate, ANAVEX 2-73, DMT (N, N-Dimethyltryptamine) , AN VEX 1-41, DHEA BD1031, BD1052, Pentoxyverine, UMB23, UMB41, UMB82 , Ditolylguanidine, 4-phenyl-l- ( 4- phenylbutyl) piperidine) and ANAVEX 3-71.

14. The method of any one of claims 1-12, wherein the modulator is at least one member of a group comprising: Chlorpromazine, Nemonapride, Sertraline, Phenytoin (DPH) , Ropizine, ((-)-SKF- 10047) , N- [2- (Piperidinylamino) ethyl] -4- iodobenzamide, Allylnormetazocine, testosterone, pregnenolone, nemopramide, Eliprodil (SL82.0715), LS-127, LS-137, SV 89, SV 156, pimozide, propranolol, TC 1, SKF 83959, PD144418, Afobazole, Citalopram, Escitalopram, Ketamine, L-687,384, methylphenidate, Opipramol, and Quetiapine.

15. The method of any one of claims 1-12, wherein the modulator is at least one member of a group comprising: NE100, AC927, AZ66, BD1008, BD-1047, BD1060, BD1067, LR132, MS-377, progesterone, BD1063, BMY-14802 and E-52862.

16. The method of any one of claims 1-12, wherein the modulator is at least one member of a group comprising: UMB 100, UMB 101, UMB 103, YZ-069, NE100, AC927, AZ66, BD1008, BD-1047, BD1060, BD1067, LR132, haloperidol, reduced haloperidol, Rimcazole, Panamesine, YZ-011, Dup 734, (+)-MR 200, Metaphit, MS-377, progesterone, BD1063, SSR125047, SR31742, AC927, B Y-14802, S1RA, AZ66, CM156, E- 5842, LR172, UMB 116, and YZ-185.

17. A modulator of the Sigma-1 receptor for use in treating a subject suffering from a neurodegenerative disease or neurodegenerative disorder .

18. Use of a modulator of the Sigma-1 receptor in the manufacture of a medicament for treating a subject suffering from a neurodegenerative disease or neurodegenerative disorder.