WO2016020850A1 - Nouvelle indication thérapeutique d'antagonistes du récepteur d2 de la dopamine - Google Patents

Nouvelle indication thérapeutique d'antagonistes du récepteur d2 de la dopamine Download PDF

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WO2016020850A1
WO2016020850A1 PCT/IB2015/055937 IB2015055937W WO2016020850A1 WO 2016020850 A1 WO2016020850 A1 WO 2016020850A1 IB 2015055937 W IB2015055937 W IB 2015055937W WO 2016020850 A1 WO2016020850 A1 WO 2016020850A1
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substance
use according
dysbindin
cognitive
mice
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Francesco PAPALEO
Diego SCHEGGIA
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Fondazione Istituto Italiano Di Tecnologia
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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

Definitions

  • the present invention relates to a novel therapeutic indication for antagonists of dopamine D2 receptors, particularly antipsychotic drugs.
  • behavioural disorders associated with impaired neurological development such as schizophrenia, autistic spectrum, and attention deficit hyperactivity disorder (ADHD)
  • ADHD attention deficit hyperactivity disorder
  • DTNBP1 dystrobrevin-binding protein 1
  • DTNBP1 DTNBP1 genetic variations in DTNBP1 have been suggested to affect cognitive abilities both in humans and in mice (Burdick et al., Human Molecular Genetics, 2006, Vol. 15, No. 10 1563-1568; Karlsgodt et al., Biol Psychiatry, 201 1,69:28-34; Wolf et al., Molecular Psychiatry (2009), 1-11 ; Papaleo et al., Molecular Psychiatry (2010), 1-1). Moreover, several studies have linked genetic variations in DTNBP1 to an increased risk of developing schizophrenia. In patients affected by schizophrenia, decrease in the expression of the dysbindin-1 gene was actually detected in the hippocampus and the prefrontal cortex (PFC).
  • PFC prefrontal cortex
  • the present inventors demonstrated that a decrease in the levels of the dysbindin-1 protein increases the expression of D2, but not Dl, dopamine receptors on the surface of mice cortical neurons. Without wishing to be bound by any theory, this is probably due to an altered reinsertion of the D2 receptors on the neuronal membrane, likely caused by alterations in the lysosomal trafficking. Con- versely, the total levels of Dl and D2 receptors do not vary in the cortex of genetically engineered mice with decreased dysbindin-1 compared to wild type mice. Only the levels of D2 receptors on the cell surface are increased.
  • mice demonstrate modulation of antipsychotic drugs (such as for example risperidone) by genetic modifications which result in decreased levels of the dysbindin-1 protein in genetically modified mice, in healthy human subjects, and in patients affected by schizophrenia.
  • antipsychotic drugs such as for example risperidone
  • mice the decrease of dysbindin-1 has been studied by using heterozygous (dys+/-) or homozygous (-/-) knockout mice.
  • dysbindin-1 has been studied by using a haplotype consisting of a set of single nucleotide polymorphisms (SNPs) comprising the SNP T allele of Reference SNP cluster ID (rs) 2619538, the A allele of rs3213207, and the A allele of rs 1047631.
  • SNPs single nucleotide polymorphisms
  • dysbindin-1 polymorphisms known to be associated with schizophrenia, not con- nected with a reduction in the protein levels are rsl018381, rs2619522, rslOl 1313, rsl6876759, rs2005976, rs2619539, rs6675281, rs821616, rs909706, rs760761, rs2619528 (Corvin A et al., Neurosci Lett. 2008 Jan 31 ;431(2): 146-9; Trost S et al., Eur Arch Psy- chiatry Clin Neurosci.
  • one aspect of the present invention is a substance selected from the group consisting of antagonists of D2 dopaminergic receptors for use in the modulation of cognitive dysfunctions in a subject bearing a functional genetic variation in the DTNBPl gene capable of diminishing the levels of the dysbindin-1 protein.
  • the subject preferably suffers from schizophrenia, autistic spectrum, or attention deficit hyperactivity disorder (ADHD).
  • the decrease in the levels of the dysbindin-1 protein refers to a subject defined as not bearing any of the following SNPs: the T allele of rs2619538, the A allele of rs3213207, and the A allele of rs 1047631.
  • the genetic background of interest is defined by the haplotype consisting of the following SNPs: rs2619538-rs3213207-rsl047631.
  • Preferred substances suitable for use according to the present invention are antagonists of D2 dopaminergic receptors, such as for example antipsychotic drugs.
  • antipsychotic drugs suitable for use according to the invention are risperidone, ha- loperidol, olanzapine, clozapine, aripiprazole, quetiapine, ziprasidone, sertindole, sulpirideamisulpiride, zotepine, and combinations thereof.
  • dys +/+ mice needed more trials (p ⁇ 0.05; fig. lb) and more time (p ⁇ 0.05; fig. lc) for the resolution of the EDS compared to CD, IDS, IDS2, IDS2Re, and the EDSRe stage.
  • Figure 2 shows the results for the modulation of the executive cognitive function of attentional set-shifting by Bray haplotype (rs2619538-rs3213207-rsl047631) in healthy subjects and patients with schizophrenia treated with antipsychotic drugs.
  • Figure 3 shows that risperidone (daily dose of 0.1 mg/kg) improves the attentional set-shifting only in mice with a decrease in dysbindin-1.
  • genomic DNA was extracted from blood samples by using standard protocols.
  • SNPs present on the DTNBPl gene (rs2619539, rs3213207, rsl047631) were specially selected on the basis of initial studies (Straub RE et al., Am J Hum Genet. 2002 Aug;71(2):337-48) and further analyses that show association with schizophrenia (Williams NM et al. (2004) Arch Gen Psychiatry 61 :336-344; Bray NJ et al. (2005) Hum Mol Genet 14:1947-1954), as listed in the SZGene database (Allen NC et al. (2008) Nat Genet 40:827-834).
  • DNA samples were subjected to genetic analysis for SNPs by using custom- ized Taqman allelic discrimination assays for genotyping (Applied Biosystems) in a realtime PCR AB 17900 (Applied Biosystems).
  • genotyping the protocol recommended by the manufacturer was used.
  • allelic discrimination ABI Prism 7900 HT Sequence Detection System and version 2.1 of the SDS software (Applied Biosystems) were used. Genotypes were assigned automatically for allelic discrimination data with SDS, and manually for individual absolute quantification data, both resulting in concordance rates of 100%.
  • Each SNP TaqMan® genotyping assay contains two probes labelled at the 5' end for detecting the allele specific for the particular polymorphism of interest. In particular, probe for allele 1 displays the VIC® dye, whereas that for allele 2 displays the FAM® dye. The protocol recommended by the kits user manual was followed:
  • the allelic discrimination protocol consists of reading and normalizing the fluorescence of the allele-specific markers (FAM and VIC) with respect to the reference dye in each well.
  • the software provides a graphical representation of the intensity of the two markers for each sample (allelic discrimination plot).
  • the plot groups the samples into three classes, one for each genotypic class: samples homozygous for allele 1 for which only VIC fluorescence was detected, heterozygous samples wherein both VIC and FAM fluorescences were detected, samples homozygous for allele 2 for which only FAM fluorescence was detected.
  • dys +/- mice with reduced levels of dysbindin- 1
  • their control dys +/+ conspecifics with normal levels of dysbindin-1
  • Five dys+/- mice were excluded as they were not able to complete the test, whereas only one dys +/+ failed to finish the entire test (fig. Id). All the other mice learned to make the whole sequence of presented discriminations without any difficulty. Nevertheless, genetically modified mice with decreased levels of dysbindin-1 (that is dys +/-) took more days to complete the test (p ⁇ 0.05; fig. le).
  • dys +/- mutant mice needed more trials (p ⁇ 0.05; fig. la) and more time (p ⁇ 0.05; fig. lb) for solving the EDS stage, compared to their dys +/+ littermate controls, which is the most critical stage for assessing the executive cogni- tive abilities that are dependent on the prefrontal cortex, and is similar to that found from errors made by human subjects tested in the Wisconsin Card Sorting Test (WCST).
  • WCST Wisconsin Card Sorting Test
  • no differences relevant to dysbindin-1 genotype were detected in any other stage of the ID/ED cognitive test.
  • dys +/- mice need more time to make a choice compared to mice with normal levels of dysbindin-1 (p ⁇ 0.005, fig.
  • Bray haplotype in the DTNBP1 gene modulates the executive cognitive abilities in human beings.
  • the inventors carried out a number of experiments in order to verify whether functional genetic variants of the DTNBPl gene resulted in the same cognitive effects also in humans in a cognitive test similar to that used in mice and dependent on the prefrontal cortex.
  • DysBray -/- > DysBray +/-> DysBray +/+ were studied.
  • WCST which is largely used for measuring and testing executive cognitive functions in humans, and which is sensitive to PFC functions (Robbins TW, Roberts a C (2007) Cereb Cortex 17 Suppl 1:151-160; Barnett JH et al. (2010) Neurosci Biobehav Rev 34:1161- 1177).
  • Bray haplotype produces opposite effects on executive cognitive abilities in patients with schizophrenia. Given the deep impact of cognitive dysfunctions on the functional outcome of schizophrenia, the inventors carried out some experiments in order to verify whether Bray haplotype was able to modulate the executive cognitive abilities in patients with schizophrenia. The performances of 158 subjects who met the diagnosis criteria of the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) for schizophrenia were analysed.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders IV
  • DysBray +/- and +/+ patients bearing the haplotype that reduces the levels of dysbindin-1 obtained better cognitive results than patients without the Bray hap- lotype in the DTNBPl gene (DysBray-/-).
  • DysBray +/+ patients made fewer perseverative (p ⁇ 0.05, fig. 2d) and non-perseverative (p ⁇ 0.05, fig. 2e) errors compared to DysBray-/- patients.
  • DysBray +/+ patients were shown to have completed more categories in WCST (p ⁇ 0.05, fig. 2f) compared to DysBray-/- patients.
  • DysBray +/- patients made fewer perseverative errors (p ⁇ 0.05) than DysBray-/- pa- tients.
  • the inventors carried out further experiments to understand why, unlike healthy subjects, patients with schizophrenia bearing Bray haplotype showed better out- comes compared to non-bearing patients. It has been suggested that the effect of antipsychotic drugs taken by these patients could explain the differences in their cognitive performances dependent on genetic variations in the DTNBPl gene.
  • the murine dysbindin-1 mutant model of the inventors was used to test the effect of risperidone, one of the second-generation antipsychotics currently most used as a pharmacological therapy in patients with schizophrenia.
  • mice with reduced levels of dysbindin-1 (dys+/-) and their control conspecifics (dys+/+) were treated with 0.1 mg/kg risperidone (Ris) or the vehicle (Veh) once daily for two weeks and then were tested in the ID/ED task to assess their executive abilities of attentional set-shifting.
  • risperidone RV
  • Veh vehicle
  • One dys +/+ Veh mouse, two dys +/+ Ris mice, four dys +/- Veh mice and four dys +/- Ris mice were excluded because they failed to complete the entire ID / ED procedure (fig. 3d).
  • Dys +/- mutant mice treated with risperidone completed the test, taking fewer days than dys +/- mice treated with the vehicle (p ⁇ 0.05).
  • risperidone significantly improved the performance of dys +/- mice, in fact they completed the EDS with fewer trials (p ⁇ 0.005; fig. 3a) and less time (p ⁇ 0.05; fig. 3b) compared to the dys +/- group treated with the vehicle and to the dys+/+ groups.
  • risperidone enormously improved the executive cognitive abilities in dys +/- mice, which, otherwise, were again confirmed to be dysfunctional after treatment with the vehicle (p ⁇ 0.05; fig. 3a).

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Abstract

La présente invention concerne une nouvelle utilisation thérapeutique d'antipsychotiques et d'antagonistes du récepteur D2 de la dopamine dans la modulation de dysfonctionnements cognitifs, chez un sujet porteur d'une variation génétique fonctionnelle dans le gène DTNBP1, apte à réduire les niveaux de la protéine dysbindine -1.
PCT/IB2015/055937 2014-08-06 2015-08-05 Nouvelle indication thérapeutique d'antagonistes du récepteur d2 de la dopamine WO2016020850A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090233942A1 (en) 2008-03-13 2009-09-17 Maria Athanasiou Genetic markers associated with response to antidepressants
US20110287417A1 (en) 2006-12-18 2011-11-24 Maria Arranz Predicting a response to risperidone
EP2570501A2 (fr) 2008-01-02 2013-03-20 Suregene Llc Marqueurs génétiques de maladie mentale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110287417A1 (en) 2006-12-18 2011-11-24 Maria Arranz Predicting a response to risperidone
EP2570501A2 (fr) 2008-01-02 2013-03-20 Suregene Llc Marqueurs génétiques de maladie mentale
US20090233942A1 (en) 2008-03-13 2009-09-17 Maria Athanasiou Genetic markers associated with response to antidepressants

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