The present invention relates to an antipsychotic drug which comprises an N-acyl amino acid derivative as an active principle.
In 1951, H. Laborit found an antipsychotic action of chlorpromazine, and in 1952, J. Delay and P. Deniker introduced the compound into a medical treatment of schizophrenia. Then, they found clinical effectiveness, medical therapy of schizophrenia was started. Thereafter, antipsychotic drugs which comprise phenothiazine derivatives such as chlorpromazine and butyrophenone derivatives such as haloperidol have been developed.
In 1975, P. Seeman et al. and S. H. Snyder et al. found that that antipsychotic drugs could reveal the function by blocking dopamine receptor and by controlling dopamine activity. Further, in case of schizophrenia, since it was known that dopamine activity was excessively increased in the mesocortical system and the mesolimbic system, a dopamine hypothesis had appeared.
An antagonist of dopamine gives splendid effect to positive symptoms of acute schizophrenia, such as hallucination, delusion, thought disorder, excitation, etc.. On the other hand, no medicines for treating negative symptoms of chronic schizophrenia, such as feeling insensibility, desolation conditions, etc. are produced, so that the treatment of the chronic schizophrenia depends on an occupational therapy or life guidance under existing circumstances.
Epilepsy is a chronic disease repeating spastic fits. It has become apparent that antiepileptics act on a benzodiazepine receptor which conjugates with a .gamma.-aminobutyric acid (GABA) receptor and increases the action of the GABA receptor to show antiepileptic functions.
On the other hand, schizophrenia is a disease principally showing acute positive symptoms such as hallucination, delusion, etc. and chronic negative symptoms such as feeling insensibility, lowering of volitions, etc.. In recent years, it has been considered that the schizophrenia is caused by depression of an N-methyl-D-asparatate (NMD-Asp) receptor which is a glutamic acid receptor (Clinical Neuropharmacology, 12(1), 1-13, 1989).
In Japanese Patent Publication No. 1-37373 and Japanese Patent Publication No. 63-9491, 2-pentanoyl amino acetic acid and 2-n-pentyl amino aceto amide having anticonvulsant functions for convulsion induced with bicuculline which is an antagonist specific for GABA were disclosed. It has become apparent that these compounds show the anticonvulsant functions via a GABA system (Biochemical Pharmacol., 32, 2751-2755, 1983).
However, these compounds are useful for epilepsy, and do not act on schizophrenia.
Since phencyclidine causes a person to have schizophrenia conditions of positive symptoms and negative symptoms, the study of intracelebral effects of phencyclidine is useful as means of systematically learning the beginning of both symptoms and finding the medicines for treating the negative symptoms. Lately, concerning an in-vitro test in elecrophysiological and biochemical study, phencyclidine has an effect on a specific binding site in an ion channel which conjugates with an excitatory amino acid receptor of an N-methyl-D-asparaginic acid type. As a result, it is found that nervous conduction via the N-methyl-D-asparaginic acid receptor is inhibited without a rival. On the other hand, since the N-methyl-D-asparaginic acid receptor has a strychnineinsensitive glycine binding site (an allosteric site), effective agents such as glycine, D-serine, D-alanine, etc. are differed from medicines such as phencyclidine and the like. These agents are known as a material promoting the action of N-methyl-D-asparaginic acid receptor.
Antipsychotic drugs such as said chlorpromazine give unsatisfactorily side effect, for example, myogelosis, mouth dry, sleepiness and constipation. In addition, even if the above amino acids such as glycine and the like are dosed in a living body, these can not pass through blood brain barrier and can not well act as an activator of the N-methyl-D-asparaginic acid receptor.