Treatment of parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor

a technology of dopamine signal and pde 10, which is applied in the field of parkinson's disease and dopamine signal enhancement using pde 10 inhibitors, can solve the problems of unknown parkinson's disease symptoms, achieve the effects of alleviating parkinson's disease symptoms, suppressing the decomposition of the second messenger, and stimulating the dopaminergic receptor

Inactive Publication Date: 2013-03-21
MITSUBISHI TANABE PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034]The present inventors have found out that a compound having an inhibitory activity on phosphodiesterase 10 has an effect of enhancing an activity caused by L-dopa administration in Parkinson's disease model animals, that it can be used for alleviating the symptoms specific for Parkinson's disease, and that it enhances dopamine signals in the brain, whereby the present invention has completed.
[0037]It is thought that action mechanism for the pharmaceutical or the therapeutic method of the present invention is outlined as follows. Accordingly, the PDE10 inhibitor as an active ingredient acts on neurons expressing dopaminergic receptors in the brain, inhibiting an activity of PDE10, thereby suppressing decomposition of the second messenger, cAMP. It is thought that, through this action, signals caused by stimulation of the dopaminergic receptor (hereinafter referred to as dopamine signals) can be enhanced, and an effect of alleviating symptoms of Parkinson's disease is exhibited.

Problems solved by technology

Further, when dopamine is decreased, a balance is lost between dopamine and acetylcholine, which is another neurotransmitter, leading to the symptoms of Parkinson's disease.
However, a long-termed administration of L-dopa causes complications such as dyskinesia, etc.
Further, it has a problem of instability such as wearing-off phenomenon, on-off phenomenon, etc., or problem of showing unexpected reaction or involuntary movements.
However, it has not been known, until today, to apply PDE10 inhibitor for treatment of Parkinson's disease.

Method used

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  • Treatment of parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor
  • Treatment of parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor
  • Treatment of parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor

Examples

Experimental program
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Effect test

example 1

Measurement of PDE10 Inhibitory Activity

[0119](1) Enzyme Preparation of PDE10 (PDE10A)

[0120]According to the methods described in Fujishige et al. (Fujishige et al., Eur. J. Biochem., vol. 266, pp. 1118-1127, 1999; and Mukai et al., Br. J. Pharmacol., vol. 111, pp. 389-390, 1994), the enzyme PDE10A was isolated and prepared as follows.

[0121]At first, corpus striatum was excised from bovine whole brain (Japanese Black Cattle, purchased from Tokyo Shibaura Zoki, co., Ltd.), and washed with ice-cold saline (0.9% sodium chloride). After the tissues were cut in a proper size, it was frozen by liquid nitrogen, and stored at −80° C.

[0122]To about 1.3 g of this tissue sample was added 8 ml of an ice-cold homogenization buffer I (20 mM Tris-HCl, pH 7.5, 2 mM magnesium acetate, 0.3 mM calcium chloride, 1 mM dithiothreitol, 1.3 mM benzamidine, 0.2 mM phenylmethylsulfonyl fluoride), and the resultant mixture was homogenized by Polytron homogenizer (PT10 / 35; available from KINEMATICA) for about ...

example 2

Measurements of Inhibitory Activities for PDE Families Other than PDE 10

[0135](1) Preparation of Enzymes of PDE Families Other than PDE10

[0136]According to the methods described in the literature, the enzyme of PDE families other than PDE10 were isolated and prepared as follows.

Enzyme preparations for PDE1, 2, 3, 4, 5 and 6 were done according to the method described in Kotera et al. (Biochem. Pharmacol., vol. 60, pp. 1333-1341, 2000).

[0137]Enzyme Preparation of PDE1

[0138]Ventricle was excised from SD rat anesthetized with sodium pentobarbital (Nihon SLC, about 300 g), and washed with 100 ml of ice-cold saline 3 times. After the tissues were cut in approximately 1 g, it was frozen by liquid nitrogen, and stored at −80° C.

[0139]To about 5 g of this tissue sample was added 16 ml of an ice-cold homogenization buffer I, and the resultant mixture was homogenized by Polytron homogenizer for 3 minutes. The homogenate was centrifuged at 8000 rpm, at 4° C. for 20 minutes, and the obtained su...

example 3

Expression of PDE10 in the Brain

[0204](1) Expression of PDE10 (PDE10A) in the Human Brain (Detection by PDE Activities)

[0205]Respective parts of the human brain (frontal lobe, temporal lobe and nucleus accumbens) were examined with respect to the presence or absence of PDE10 (PDE10A) activities. PDE10 (PDE10A) activities in the respective parts of the brain were detected by measuring inhibitory activities using PDE10 (PDE10A) specific inhibitor, as follows.

[0206]As the PDE10 (PDE10A) specific inhibitor, a compound showing an excellent selectivity, exhibiting weak or no inhibitory activities towards PDE families other than PDE10 was used.

[0207]As a reference, to 14.8 mg of corpus striatum of rat brain was added 1 ml of a homogenation buffer (20 mM Tris-HCl, pH 7.5, 2 mM magnesium acetate, 0.3 mM calcium chloride, 1 mM DTT, 1.3 mM benzamidine, 0.2 mM PMSF), and the mixture was homogenated by a sonicator, to give a homogenate. One μL of this homogenate was used as an enzyme solution, t...

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Abstract

The present invention relates to a therapeutic or prophylactic method for treating Parkinson's disease by administering an effective amount of a compound having a phosphodiesterase 10 inhibitory activity; and also relates to a pharmaceutical composition for treatment or prophylaxis of Parkinson's disease comprising as an active ingredient a compound having a phosphodiesterase 10 inhibitory activity. Moreover, the present invention relates to a method for enhancing dopamine signal in the brain, which comprises administering an effective amount of a compound having a phosphodiesterase 10 inhibitory activity; and also relates to pharmaceutical composition for enhancing dopamine signal in brain comprising as an active ingredient a compound having a phosphodiesterase 10 inhibitory activity.

Description

[0001]The present application is a 37 C.F.R. §1.53 (b) divisional of, and claims priority to, U.S. application Ser. No. 12 / 647, 880 filed Dec. 28, 2009. Application Ser. No. 12 / 647,880 is a Continuation of Ser. No. 10 / 726,634 (now abandoned) filed Dec. 4, 2003, which application claimed the benefit of U.S. provisional application No. 60 / 430,641, filed Dec. 4, 2002, U.S. provisional application No. 60 / 430,642, filed Dec. 4, 2002, and U.S. provisional application No. 60 / 488,375, filed Jul. 21, 2003. The entire contents of each of these applications is hereby incorporated by reference.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to a novel method for treatment or prophylaxis of Parkinson's disease. The present invention also relates to a novel agent for treatment or prophylaxis of Parkinson's disease. Further, the present invention relates to a novel method for enhancing dopamine signals in the brain.[0004]2. Prior Art[0005]Parkinson's d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/198A61K31/137A61K31/517A61K31/165A61K31/4985A61K31/352A61K31/55
CPCA61K31/198C07D403/14A61K31/137A61K31/55A61K31/165A61K31/4985A61K31/517A61K31/48A61K31/352A61K2300/00
Inventor KOTERA, JUNSASAKI, TAKASHIKITAZAWA, TAKEOISHII, TAKETOSHIMORIMOTO, HIROSHIYAMADA, HARUTAMI
Owner MITSUBISHI TANABE PHARMA CORP
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