Antagonists of the cannabinoid receptor CB1 for use in the treatment of diseases associated with neuronal dendritic abnormalities

1. A method of treatment of a disease associated with neuronal dendritic abnormalities in a subject in need thereof or of delaying the onset or slowing the development of symptoms of a disease associated with neuronal dendritic abnormalities in a subject at increased risk of developing a disease associated with neuronal dendritic abnormalities, comprising administering to said subject a therapeutically effective amount of an antagonist of the cannabinoid receptor CB1 selected from a neutral antagonist or an inverse-agonist of the cannabinoid receptor CB1.

2. The method according to claim 1 , wherein said antagonist is selected from the group consisting of the compounds of Table 1 or pharmaceutically acceptable salts thereof.

3. The method according to claim 2 , wherein said antagonist is the compound 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof.

4. The method according to claim 2 , wherein said antagonist is selected from the group consisting of:

1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide,

(6aR,10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran,

N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-butanyl]-2-methyl-2-{[5-(trifluoromethyl)-2-pyridinyl]oxy}propanamide,

5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide,

4S-(−)-3-(4-chlorophenyl)-N-methyl-N′-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

(±)-N-{1-[bis(4-chlorophenyl)methyl]-3-azetidinyl}-N-(3,5-difluorophenyl)-methanesulfonamide,

1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-(ethylamino)piperidine-4-carboxamide,

and

(±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-piperidinyl)-4,5-dihydro-1H-pyrazole-3-carboxamide

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 2 , wherein said antagonist is selected from the group consisting of:

Compound AM4113 of formula:

Compound VCHSR1 of formula:

Compound AM6527 of formula:

Compound BPR0432 of formula:

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 , wherein the disease is associated with pyramidal neuronal dendritic abnormalities.

7. The method according to claim 1 , wherein the neuronal dendritic abnormalities are aberrant morphology and/or number of dendritic spines.

8. The method according to claim 7 , wherein the number of dendritic spines is increased.

9. The method according to claim 8 , wherein the number of immature spines (thin and stubby spines) is increased.

10. The method according to claim 1 , wherein said antagonist is administered orally.

11. The method according to claim 1 , wherein said antagonist is administered intraperitoneally.

12. The method according to claim 1 , wherein said disease is selected from the group consisting of Down's syndrome, Angelman's syndrome, Rett syndrome and tuberous sclerosis.

13. The method according to claim 1 , wherein said disease is caused by mutation invalidating the FMR1 gene.

14. The method according to claim 1 , wherein said disease is Fragile X syndrome.

15. The method according to claim 4 , wherein said disease is selected from the group consisting of Down's syndrome, Angelman's syndrome, Rett syndrome and tuberous sclerosis.

16. The method according to claim 4 , wherein said disease is caused by mutation invalidating the FMR1 gene.

17. The method according to claim 4 , wherein said disease is Fragile X syndrome.