IT9020418A1 - THERAPEUTIC AGENT ACTIVITIES ON THE CENTRAL NERVOUS SYSTEM - Google Patents

Description

Description of the industrial invention entitled: "THERAPEUTIC AGENT ACTIVITIES ON THE CENTRAL NERVOUS SYSTEM"

DESCRIPTION OF THE INVENTION

The present invention relates to the use of nicotinylalanine as a therapeutic agent for the treatment of diseases of the Central Nervous System.

Nicotinylalanine, whose structural formula is shown below,

has been known for some time: about 30 years ago it was believed to be a metabolic product of tryptophan and an intermediate metabolite of the so-called kynurenine pathway, that is, that of metabolic events capable of opening the indole ring of tryptophan and leading to the formation of NAD.

However, it was quickly ascertained that this was not experimentally sustainable and that nicotinylalanine, although not a metabolite of tryptophan, could nevertheless interfere in an inhibitory sense with its metabolism at the level of at least two enzymatic systems: kynureninase and kynurenine hydroxylase (Decker et al. al., J.B.C., 1963; 238; 1049-1053).

These enzymes catalyze the metabolism of kynurenine first to 3-hydroxyquinurenine and subsequently to 3-hydroxyantranilic acid, the direct precursor of quinolinic acid.

Much more recently it has been observed that 3-hydroxyquinurenine can be toxic to neuronal cells in culture and that quinolinic acid is a toxin capable of exciting neurons and possibly causing their death both in "in vitro" and "in vivo" preparations. . (Stane and Connick; Neuroscience, 1985; 15; 597-618).

The underlying mechanism of this neuronal death is that of a competitive inhibition of kynurenine hydroxylase and kynureninase. In the metabolic pathway that leads from tryptophan to NAD, kynurenic acid can also be formed through a simple enzymatic process that involves the intervention of a transaminase.

This is a molecule capable of inhibiting the excitotoxic action of quinolinic acid as it agonizes its effects on NMDA receptors with a modulatory mechanism that is now sufficiently clear (Moroni et al., Eur. J. Pharmac., 1989; 163; 123 -126).

The metabolic path of tryptophan and the so-called kynurenine pathway is reported below.

From the biochemical knowledge available so far, no therapeutic application of nicotinylalanine was foreseeable, which in fact, despite being known for decades, has never been the subject of studies aimed at pharmacological use.

It has now been found that nicotinylalanine prevents the accumulation of toxic tryptophan metabolites and increases the synthesis of metabolic compounds having sedative activity, as demonstrated by the following pharmacological experiments.

Rats or mice treated with lipopolysaccharides extracted from bacteria have concentrations of quinolinic acid and kynurenic acid three times higher in their biological fluids and in their brains than controls. This is due to the induction of the indolamine-2, 3-dioxygenase enzyme and therefore to an increased formation of all the molecules originating from the kynurenine pathway. When, in addition to bacterial lipopolysaccharides, nicotinylalanine (50-1000 mg / kg i.p.) is also administered, the increase in the concentrations of quinolinic acid is significantly reduced while that of kynurenic acid is strongly increased. In other words, nicotinylalanine facilitates the formation of a metabolic product of tryptophan with antagonistic properties on the receptors for excitatory amino acids while reducing that of an excitotoxic molecule. Similar results were observed when appropriate doses of nicotinylalanine were administered together with tryptophan.

In addition, in the DBA / 2 mouse, the simultaneous administration of tryptophan 200 mg / kg i.p. and nicotinylalanine 200 mg / kg i.p. causes sedation and protects animals from audiogenic seizures. This suggests that the cerebral accumulation of kynurenic acid (which we have demonstrated) is associated with the same behavioral manifestations of the animal.

From the above it is evident that nicotinylalanine can be advantageously used in a variety of pathologies involving the Central Nervous System and characterized by an abnormal increase in tryptophan metabolism.

Examples of such conditions in which an imbalance exists between excitotoxic molecules and their modulators or antagonists are:

1) All infectious diseases of both bacterial and viral nature (including AIDS). Under these conditions, the activation of the immune system causes an increase in the flow of tryptophan through the kynurenin metabolic pathway and consequently causes a cerebral accumulation of quinolinic acid (Heyes et al., Annals Neurol., 1989; Heyes et al. , 1988; 51; 1946-1948;

2) Neoplastic diseases, especially those of the immune system (lymphomas);

3) Treatments with interferon and / or interleukins (Brown et al., Cancer Res., 1989; 49; 4941-4945);

4) Many convulsive forms (Lapin et al., Epilepsia, 1981; 22; 257-265);

5) Huntington's chorea and other degenerative diseases such as m. Parkinson's and senile dementia (Schwarts et al., Life Sciences, 1984; 35; 19-23);

6) Hepatopathies (Moroni et al., J. Neurochem., 1986; 46; 849-874);

7) Alterations of the sleep-wake rhythm;

8) Neuropsychiatric alterations of pellagra and other vitamin deficiencies;

9) Chronic alcoholism in which there is a reduction of the cerebral contents of kynurenic acid personal observations;

10) Numerous situations of psychiatric interest in which alterations of the metabolism of tryptophan have been anxiously documented (depression, schizophrenia, eoe.);

11) Cerebral stroke;

12) High pressure syndrome and essential tremor.

For the foreseen therapeutic uses, nicotinylalanine or its physiologically equivalent derivatives (salts, esters, non-toxic amides) will generally be administered in doses ranging from 10 to 100 mg / kg / day. However, the exact dosage will depend on several factors such as the patient's condition, type and severity of the disease.

Administration will be performed orally, rectally or parenterally using conventional pharmaceutical formulations such as those described in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co-, N.Y. USA, 17 <a> Ed., 1985.

Nicotinylalanine can be prepared according to the methods described in J. Biol. Chem. 238, 1049 (1963) and J. Qrg. Chem. 28, 383 (1953). While the use of the molecule in the natural spherical configuration L is preferred, the invention relates to the use of the racemic form and the D form of nicotinylalanine.

Claims (3)

CLAIMS 1. Use of nicotinylalanine or its physiologically equivalent derivatives as therapeutic agents. 2. Pharmaceutical compositions containing nicotinylalanine or a physiologically equivalent derivative thereof as the active ingredient. 3. Use of nicotinylalanine for the preparation of a medicament for the treatment of conditions characterized by an abnormal increase in the metabolism of tryptophan.