WO2000044360A2

WO2000044360A2 - Drugs for treatment of psychiatric and brain disorders

Info

Publication number: WO2000044360A2
Application number: PCT/GB2000/000137
Authority: WO
Inventors: David Frederick Horrobin
Original assignee: Laxdale Limited
Priority date: 1999-01-27
Filing date: 2000-01-20
Publication date: 2000-08-03
Also published as: WO2000044360A3; GB9901808D0; AU3063800A

Abstract

Pharmaceutical preparations which comprise compounds which can be metabolised by FACL enzymes are disclosed. Those compounds metabolised by FACL-4 to Coenzyme A derivatives are preferred. Highly unsaturated fatty acids (HUFAs) and their derivatives are suitable such compounds. The most preferred compound is eicosapentaenoic acid. The psychiatric disorders to be treated are schizophrenia, schizo-affective disorders, mania, depression, bipolar disorders, ADHD, anxiety and panic attacks, social phobias, Alzheimer's disease and other dementias, epilepsy, Parkinson's disease, stroke transient ischemic attack, multiple sclerose, Huntington's disease, and other neurodegenerative disorders.

Description

DRUGS FOR TREATMENT OF PSYCHIATRIC AND BRAIN DISORDERS

Traditional targets for drug actions in psychiatric and neurological disorders have for the most part been neurotransmitters and their receptors. Neurotransmitters are released from one nerve cell and act on another and so are responsible for much of the communication between nerve cells which constitutes brain activity. It is therefore reasonable that these should be targets and almost all drug development in psychiatry and in brain disorders has concentrated on the neurotransmitters and their receptors.

However, when a neurotransmitter occupies a receptor on the outside of a nerve cell, that is only the beginning of the response of that cell. Following receptor occupation a whole series of events take place which go under the name of cell signalling or signal transduction and which determine the way in which nerve cells respond. It is now emerging that one of the ways in which nerve cells react is by activating an enzyme known as phospholipase A2 (PLA-) . This occurs in response to occupation of receptors by dopamine (Vial and Piomelli, J Neurochem 1995; 64: 2765-72) by acetyl choline, by glutamate, by serotonin and by GABA. It also occurs in response to physical and chemical injuries to the brain of many different types. These include hypoxia and anoxia, ischaemia, trauma, cytokines released during inflammation and immunological activation, beta- amyloid which accumulate in the brain during Alzheimer' s disease and many other situations. Activation of PLA₂ is thus a common mechanism of neuronal response in many situations. It is also a common mechanism of initiating inflammatory reactions in all other organs. It plays a role in such inflammatory conditions as the various forms of arthritis, inflammatory diseases of the skin such as eczema and psoriasis, asthma, and inflammatory disorders of the kidneys, gastrointestinal organs, reproductive tract and other tissues.

PLA, is an enzyme which acts on membrane phospholipids to generate two products, a fatty acid which is released from the Sn2 position of the phospholipid, and a lyso-phospholipid (LyPL) which is a phospholipid without a fatty acid attached to the Sn2 position. In brain the fatty acids attached to the Sn2 position are almost all highly unsaturated fatty acids (HUFAs) with 3 to 6 double bonds in the cis-configuration. The most important brain HUFAs in terms of quantity are arachidonic acid (AA) and docosahexaenoic acid (DHA) . Others which are present in smaller amounts but which may have very important cell signalling roles include eicosapentaenoic acid (EPA) , dihomogammalinolenic acid (DGLA), docosapentaenoic acid n-3 (DPA-n-3) and adrenic acid (AdrA) .

The phospholipids themselves are important components of all nerve cells and are relatively stable structures. In themselves they are not highly biologically active and the HUFA attached to them are relatively resistant to oxidation. Oxidation is always a problem since the highly unsaturated nature of the HUFAs makes them susceptible to attack.

The situation is very different after the action of PLA- . The two molecules which result, LyPL and HUFA, are both very highly reactive. LyPLs have many actions on cell functions and can also be highly destructive to membranes. HUFA themselves also have many cellular actions. They can also be converted to related highly active materials such as prostaglandins, leukotrienes, hydroxy acid and other eicosanoids. Furthermore they can be readily oxidised to a wide range of free radicals.

While LyPLs and HUFAs are obviously important in orchestrating the responses of nerve cells to a wide range of stimuli, it is also important that their actions should be limited to the time immediately following the signal. If the effects are prolonged, cell damage and death are likely to occur. It is therefore vital that the highly active molecules should be eliminated as quickly as possible.

The reactions which do this in the brain, and indeed in other tissues, have been well characterised (figure 1) . First the HUFA is linked to Coenzyme A to give HUFA-Coenzyme A. This is one of the general class of fatty acids linked to coenzyme A known as acyl-CoA. The enzymes which perform this reaction are known fatty acid coenzyme-A ligases (FACL) . They can also be called acyl-CoA synthetases. An enzyme which is important in .the human brain and which links HUFAs to coenzyme A is known as FACL-4 (Y Cao et al, Cloning expression and chromosomal location of human long-chain fatty acid-CoA ligase (FACL-4) . Genomics 1995; 49: 327-330) . This removes the very highly active free HUFAs. Other FACLs, including FACL-1, and particularly FACL-2 and FACL-3 are also found in brain and may contribute to the overall result. Methods of regulating the synthesis and function of the FACL group of enzymes are beginning to be recognised. For example, it has been shown that the synthesis of FACL-1 can be inhibited by endotoxin and cytokines (RA Memon et al, Am J Physiol 275: E64-72, 1998) .

The second step is the linking of the HUFA back to the LyPL by an enzyme group known as acyl-coenzyme A: lysophospholipid acyl- transferase (ACLA) . In the process, coenzyme A is released, the stable phospholipid is reformed and the free HUFA, HUFA-coenzyme A, and LyPL activities are all terminated.

According to the present invention, FACL-4 is proposed as a good target for the actions of drugs which will be able to treat a wide range of psychiatric and neurological disorders in which there is evidence of increased PLA, activity. These disorders include schizophrenia, bipolar disorder and depression, mania, panic disorder and anxiety, social phobias, epilepsy, stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease and other dementias including prion-related dementias, Huntington' s disease and other neurodegenerative disorders. Many other illnesses, particularly those where inflammation is important, are likely to benefit by activation of FACL-4 since PLA, activation is a common feature of them all. In all these conditions PLA₂ and related phospholipases are activated, leading to formation of free HUFAs and LyPLs which can cause and prolong the inflammatory response. Removal of the free HUFAs by FACL-4, or one of the other FACL group, and the subsequent linking of the HUFA to LyPL to terminate the activation cycle, will be an important method of stopping inflammation. The other diseases include inflammatory illnesses affecting any organ, including the bones and joints, skin, kidneys, respiratory system, gastro- intestinal tract, urinary tract, eyes, ears, reproductive organs, oropharynx, and generalised reactions such as allergies and septic shock. Activation of other FACL enzymes, especially FACL- 2 and FACL-3 will have similar desirable effects.

The present inventor has discovered that FACL-4 is important in schizophrenia. In schizophrenia there is reduced incorporation of HUFAs into membrane phospholipids, there are increased levels of LyPL, and there is increased formation of HUFA oxidation products. Moreover, a family have recently been described with a complete absence of FACL-4. This produced severe mental retardation and a range of minor physical abnormalities including mid-face hypoplasia and high arched palate which have been reported as being characteristic of schizophrenia. However, the publication made no reference to any possible association with schizophrenia or other psychiatric diseases (Piccini M et al, Genomics 1998; 47: 350-358). Because activation of PLA- is important in psychiatric and central nervous system disorders other than schizophrenia, this method will be valuable in treating these other disorders as well.

Three broad classes of drugs are likely to be active in enhancing the efficacy of FACL-4 in terminating the consequences of PLA, action. These are:

1. Drugs which can bind to FACL-4, be converted to a drug-CoA derivative and be incorporated into LyPL to produce a stable phospholipid, so removing LyPL.

2. Drugs which can activate FACL-4, by binding to an allosteric regulatory site or by some other means. As a result, the sequence of events noted in (1) may be triggered, removing free HUFAs and LyPLs from the cytoplasm.

3. Drugs which can induce FACL-4 synthesis, again triggering the sequence of events noted in (1) .

The binding characteristics of the active site of human FACL-4 are known in part (Cao et al, Genomics 1995; 49: 327-330). The binding efficacies of certain fatty acids can be ranked as shown below. The ranking was obtained by binding radioactive AA with FACL-4 and looking at displacement of that activity by unlabelled fatty acids. EPA 85.8%

7ΛA 79.5%

DHA 52.8%

Oleic 33.3%

Alpha-linolenic 26.2%

Palmitic 16.3%

Linoleic 4.6%

Thus EPA is the fatty acid which most readily forms CoA derivatives. EPA itself, or stable or other derivatives of EPA such as those described by Berge et al (N Willumsen et al, Biochem Biophys Acta 1369: 193-203 1998) are ^■ thus preferred compounds in the first category although other lipids are also likely to have activity. Derivatives of HUFAs with three or more double bonds and 18 to 22 carbon atoms bind effectively and are preferred embodiments.

Figure 1 shows the PLA, cycle which has been described in the text .

Claims

1. Pharmaceutical preparation comprising compounds which can be metabolised by FACL enzymes and particularly by FACL-4 to Coenzyme A derivatives.

2. Pharmaceutical preparation according to claim 1 comprising HUFAs or derivatives of HUFAs.

3. Pharmaceutical preparation according to claim 2 in which the HUFA has three or more double bonds and 18 to 22 carbon atoms .

4. Pharmaceutical preparation according to claim 2 or 3 comprising EPA or derivatives of EPA.

5. Pharmaceutical preparation comprising compounds which activate FACL-4 or other FACLs by binding to an allosteric site on FACL-4 or other FACLs or by other means such as changing its configuration or changing the levels of activators.

6. Pharmaceutical preparation containing compounds which induce the synthesis of FACL-4 or other FACLs.

7. Pharmaceutical preparation according to any preceding claim for the treatment of psychiatric and brain disorders.

8. Pharmaceutical preparation according to claim 7 for the treatment of schizophrenia, schizo-affective disorders, schizotypal disorder, mania, depression, bipolar disorder, ADHD, anxiety and panic attacks, social phobias, Alzheimer's disease and other dementias, epilepsy, Parkinson's disease, stroke, transient ischaemic attack, multiple sclerosis, Huntington' s disease and other neurodegenerative disorders.

9. Pharmaceutical preparation according to any of claims 1 to 6 for the treatment of any inflammatory disorder of any organ in which phospholipase A₂ or any related phospholipase is activated.

10. Use of a compound which can be metabolised by FACL-4 or other FACL to Coenzyme A derivatives in the preparation of a medicament for the treatment of psychiatric and brain disorders.

11. Use of a compound which can be metabolised by FACL-4 or other FACL to Coenzyme A derivatives in the preparation of a medicament for the treatment of any inflammatory disorder of any organ in which phospholipase A, or any related phospholipase is activated.