EP1773306A1

EP1773306A1 - Medicament for the treatment of central nervous system disorders

Info

Publication number: EP1773306A1
Application number: EP05793762A
Authority: EP
Inventors: Philippe Bernard; Fabrice Trovero
Original assignee: Key OBS; Greenpharma SAS
Current assignee: Key OBS; Greenpharma SAS
Priority date: 2004-07-26
Filing date: 2005-07-26
Publication date: 2007-04-18
Also published as: CN101014325A; WO2006018538A1; FR2873294B1; JP2008507577A; FR2873294A1; US20080194631A1; CA2575848A1

Abstract

The invention relates to the use of a molecule either alone or in a combination selected from the group of molecules having a simultaneous antagonist action on alpha-noradrenergic, NMDA glutamatergic and 5HT2 serotoninergic receptors, for the preparation of a medicament that is intended for the treatment of central nervous system pathologies.

Description

MEDICINE FOR TREATING DISORDERS IN THE SYSTEM

CENTRAL NERVOUS

The pharmacological treatment of addiction is a major public health issue. Long oriented towards cessation assistance in opiate addiction, this type of treatment is also necessary to counter the abuse of other products such as psychostimulants, tobacco or alcohol. The current pharmacopoeia has therefore developed around replacement products (nicotinic patches, opiate analogues ...) whose main mode of action is to limit the physical symptoms induced by weaning. However, there are very few substances that aim to counter the states of psychological dependence, ie the irrepressible need (or "craving") of the product. This state of dependence is much more robust and obviously represents the major factor of relapse.

Current treatments

Heroin addiction

The treatment of physical signs of withdrawal is the first treatment in detoxification.

Substitutes can be used with appropriate doses to counteract withdrawal symptoms.

Clonidine

The most widely used product for this purpose is clonidine, an alpha2-adrenergic receptor agonist generally used in the treatment of hypertension. Its action on alpha2-adrenergic receptors reduces the hyper-excitability of neurons noradrenergic and consequently limits the effects of stopping opioid use on the autonomic system.

Methadone and levomethadyl acetate Methadone and levomethadyl acetate are two μ-type opioid receptor agonists. Due to slow kinetics of action, methadone causes significant dependence. One of the interests of this type of treatment is to obtain a "controlled" consumption of opioid substance. Buprenorphine

It is a partial agonist of μ-type opioid receptors and a G-type receptor antagonist. Discontinuation of treatment results in withdrawal syndrome. The product exists in tablets (Temgesic ^® , pain treatment) and the crushing of the tablets can give rise to intravenous administrations, sought by the addict to increase the euphoric effects. The Temgesic ^® form has been replaced by a "high dosage" dosage form, Subutex ^® .

Smoking treatment

Nicotine substitution via patches or chewing gums is the only substitution therapy that has shown some effectiveness.

Bupropion has recently been proposed in the treatment of smoking. It is an antidepressant that acts by increasing the release of norepinephrine without altering its recapture. Bupropion is also a dopamine reuptake inhibitor, which may explain its "anti-craving" properties. Note also that bupropion is a receptor antagonist central nervous system, which may also contribute to its effectiveness. Nevertheless, clinical studies do not seem to indicate a significant therapeutic effect.

Treatment of addiction to psychostimulants

Cocaine causes a strong psychological dependence against which no drug has yet shown real effectiveness. Tracks are proposed. Opioid agonists used in heroin withdrawal (buprenorphine and methadone) have been tested for cocaine withdrawal assistance. Problems related to crack use are mainly treated with anxiolytics and sedative neuroleptics to counter anxiety and hyperexcitability.

The treatment of alcoholism

Pharmacological treatments are proposed in the treatment of alcoholism. Nevertheless, at present there is no satisfactory treatment. Opiate antagonists

Opioid systems play a key role in regulating drinking behavior by contributing to the reinforcing effects of alcohol intake. Recall that opiates stimulate the activity of dopaminergic systems. Naltrexone, an opioid antagonist, has been tested in clinical trials. Studies have shown that naltrexone decreases alcohol intake, frequency of relapse, and desire to drink, particularly in the case of severe alcohol abuse. It is thus the first pharmacological agent against alcoholism which acts otherwise than by triggering a phenomenon of aversion. the

Unfortunately, the use of naltrexone is limited because of its gastrointestinal side effects (nausea, vomiting, loss of appetite) (O'Malley et al., 1992, Volpicelli et al., 1992; Kranzler et al., 2000 Naltrindole

It is an δ-type opiate receptor antagonist, which has shown some efficacy in animal models. Acamprosate Although its mechanism of action is not fully understood, a body of evidence suggests that the action of acamprosate passes through a modulation of glutamatergic transmission. It seems that the molecule is effective, at least in the treatment of withdrawal symptoms. Its efficacy with respect to alcohol cravings is still debated. Serotoninergic antidepressants

Serotoninergic transmission also plays an important role in the pathophysiology of alcohol dependence. Serotonin reuptake inhibitors are antidepressants that have been tested in the treatment of alcoholism (Naranjo et al., 1984, 1987 and 1990). Therapeutic trials with these serotoninergic substances gave varying results, clinical studies showing no real efficacy. Benzodiazepines

Benzodiazepines are the most used drugs for alcohol withdrawal (for review, Lejoyeux et al., 1998). Benzodiazepines are used effectively at weaning. This effectiveness is discussed over the long term, especially since Patients are continuing this type of treatment to combat symptoms of abstinence such as anxiety and insomnia. The question of the benefit / risk ratio arises, insofar as it is a matter of replacing one abuse product with another in a patient already sensitive to addictive phenomena. Aversive medications

The first aversive drug against alcohol was disulfiram, used since 1940. When consumed simultaneously with alcohol, this product triggers unpleasant effects such as nausea, vomiting, increased blood pressure and high blood pressure. heartbeat.

The state of research

Current knowledge of neurobiology makes it possible to describe the major neurotransmission systems involved in states of dependence. In general, the key role of ascending dopaminergic systems is clearly recognized. These dopaminergic neurons have their cell bodies in a deep brain structure, the ventral tegmental area (VAT). Their projections are towards the front of the brain, mainly in the frontal cortex and in the nucleus accumbens. Most substances triggering pleasant effects, even euphoric, induce activation of these dopaminergic neurons. Repeated activation of these neurons would trigger regulatory processes that would cause the state of dependence. The state of dependence would reflect a need for sustained activation of these neurons. The search for active substances against addictions requires a good knowledge of the cerebral mechanisms that underlie addiction. The use of experimental models in animals, especially rodents, makes this research possible. In animals, addictive substances trigger locomotor hyperactivity. This hyperactivity is a very good experimental index of the motivational properties of the product. This is the case of psychostimulants such as cocaine and amphetamine. Other substances, which at certain doses induce sedative, hypnotic or relaxing effects, have more complicated patterns of behavioral responses. This is the case of alcohol and opiates that have biphasic response curves. On the other hand, for all these products, the repetition of administrations at identical doses leads to a progressive increase in the locomotor behavioral response. This phenomenon is called "behavioral awareness". If we consider that the reinforcing properties are the common denominator of these products, we can admit that this phenomenon reflects the motivational properties of a product. Conversely, other substances trigger locomotor hyperactivity in acute, without appearing behavioral sensitization after repeated administrations. These products are not reinforcing and do not lead to abusive behavior.

All products that trigger behavioral sensitization in animals have reinforcing properties and are therefore potentially abusive substances. It is interesting to note that this experimental paradigm also makes it possible to reproduce other aspects of drug addiction in humans. Indeed, behavioral sensitization is a phenomenon that is maintained after weaning for very long periods and the experimental context that triggers it reproduces the factors facilitating relapse.

(environment associated with the administration of the drug).

The analogy with addictive behavior in humans is complemented by the fact that, in animals, the self-administration of heroin also leads to sensitization of locomotor responses to heroin (De Vries et al., 1998 ).

Note that behavioral awareness is the opposite of tolerance. Indeed, in this case, it is the increase of the doses of a product which makes it possible to obtain an equivalent physiological or behavioral response. The best-known example of tolerance is that of the treatment of pain by morphine, where indeed, the evolution of the pathology forces to increase the doses to control the pain (Colpaërt, 1997). In this case of pain treatment, psychic dependence does not develop.

Many studies have been done using behavioral sensitization as an experimental model. However, the mechanisms likely to explain the long-term maintenance of the phenomenon (several months) are still unknown.

In general, behavioral sensitization has been associated with changes in the reactivity of dopaminergic neurons located in ATV and innervating the nucleus accumbens. Two elements have been dissociated, the induction of sensitization, which seems to be related to events taking place at the level of ATV, and the expression of this sensitization, which appears to be more related to the release of dopamine in the nucleus accumbens. So :

Repetition of injections of a psychoactive substance causes an increase in extracellular levels of dopamine in ATV. This effect is mediated by desensitization of dopamine D2 receptors. These phenomena could occur at the time of induction of sensitization.

- The blocking of dopamine D1 receptors present on the glutamatergic and GABAergic terminations prevents the induction of sensitization

(Stewart & Vezina, 1989, Kalivas & Duffy, 1995, Vezina, 1996).

- The blocking of ATV NMDA glutamatergic receptors prevents the induction of sensitization (Kalivas, 1995), the NMDA receptors of the nucleus accumbens are not involved (Vezina et al., 2000). - The prefrontal cortex and its projections at the ATV level play an important role (for a review see WoIf et al., 1998). The behavioral sensitization would correspond to an increase of the glutamate sensitivity released in the ATV by neurons coming from the prefrontal cortex (Tong et al., 1995), this increase is maintained 20 days after the cessation of the cocaine and does not appear not in the presence of D1 dopaminergic receptor antagonists (Kalivas & Duffy, 1998, WoIf & Xue, 1998). - Regarding the behavioral sensitization induced by repeated administration of opiates, it seems independent of D1 and D2 receptors (Vezina & Stewart, 1989; Jeziorski & White, 1995), but, as for psychostimulants, it involves glutamatergigal NMDA receptors. The prefrontal cortex is also involved (Tzschentke & Schmidt, 2000). - Stimulation of 5HT1A receptors, by decreasing the inhibitory action of serotonergic transmission on dopaminergic neurons, increases cocaine sensitization. (From the Garza & Cunningham, 2000). - Selective blockade of alpha-adrenergic receptors reduces the effects of amphetamine (Blanc et al., 1994). These results indicate that large neurotransmission systems interact during the development and maintenance of behavioral sensitization. The activity of glutamatergic, noradrenergic and serotoninergic systems seems to be particularly involved in the modulation of the dopaminergic systems that underlie this phenomenon. On the other hand, these effects have mostly been correlated with observations made in other addiction tests such as the place preference test and the drug self-administration test. Some drugs in the class of antipsychotics

(neuroleptics) have this feature of blocking different neurotransmission systems, acting in particular on dopaminergic, noradrenergic, serotoninergic receptors. These products have been tested in the treatment of drug addiction, mainly because of their ability to counteract the acute dopaminergic effects of psychostimulants such as cocaine. Unfortunately, the dopaminergic profile of these substances leads to numerous side effects, especially extra-pyramidal effects.

These results nevertheless show the close relationship between antipsychotic activity and anti-dependence efficacy. This relationship can be attributed to the involvement of the same neurotransmission systems. All of these data show that behavioral sensitization can be modulated by acting pharmacologically on different neurotransmission systems.

It is possible that a simultaneous blockage of several targeted neurotransmission systems results in a consequent reduction in the initiation and / or expression of behavioral sensitization. In other words, the combination of antagonists, in particular glutamatergic, noradrenergic and serotoninergic systems could present a synergy of action at the central level. This pharmacological action would have the effect of significantly reducing the states of dependence. In the light of what we have previously described on the effectiveness of antipsychotic substances, it is not excluded that substances that are effective against dependence also have potential antipsychotic properties. The absence of dopaminergic properties would then limit extra-pyramidal effects.

Thus, in spite of the research carried out and the treatments proposed, none makes it possible to satisfactorily treat the pathologies described above without causing significant side effects. The invention

The above-developed problems have been solved by the Applicant by testing the effects of a combination of molecules specifically targeting the glutamatergic, serotonergic and noradrenergic neurotransmission systems on behavioral amphetamine sensitization.

The associated molecules are non-selective, well known pharmacologically and do not have major side effects, they have been chosen from drugs on the market.

The invention relates to the use of a molecule alone or in a combination chosen from the group of molecules having a simultaneous antagonistic action on the alphal-noradrenergic receptors, glutamatergic NMDA and serotoninergic 5HT2, for the preparation of a medicament intended to treat pathologies of the central nervous system.

It also relates to the use as mentioned above, characterized in that the pathologies are selected from pharmaco-dependence, psychosis, smoking, disorders related to alcohol consumption, schizophrenia, psychotic states. Acute and chronic, dementia, mood disorders, attention disorders, sleep disorders, impulsivity disorders, hyperactivity, acute and chronic psychotic states, substance dependence states addictions, alcohol addiction, psychostimulant addiction, addiction to the

opiates, benzodiazepine addiction, tobacco addiction, gambling addiction.

It also relates to the use as mentioned above, characterized in that the group of molecules having a simultaneous antagonistic action on the alphal-noradrenergic, glutamatergic NMDA and serotoninergic 5HT2 receptors consists of the following molecules: 1-naphthyl) -piperazine, séganserine, olanzapine, sarprogelate, mirtazapine, aripiprazole, mepiprazole, 4-

(4-Fluorobenzoyl) -1- (4-phenylbutyl) piperidine, AMI-193, amperozide, cinanserine, clozapine, cyclobenzaprine, ketanserin, MDL 11.939, metergoline, methothepine, methysergide, mianserine, N-desmethylclozapine, piperazine, pirenperone, ritanserin, RS 102221, sertindole, SB 200646, SB 204741, SDZ SER 082, spiperone, HA 11110, amosulalol, corynanthine, HEAT, naftopidil, niguldipine, bunazosin, dapiprazole, prazosin, tamsulosin, RS 100329, RS 17053, terazosin, WB 4101, urapidil , 5-methylurapidil, (-) - MK801, (+) - MK801, (+/-) - 1- (1,2-diphenylethyl) piperidine, (2R, 3S) -Chlorpheg, (R) -4-carboxyphenylglycine, ( R) -CPP, (RS) -CPP, arcane, CGP 37849, CGP 39551, CGS 19755, D-AP5, D-AP7, DL-AP5, DL-AP7, L-AP5, loperamide, LY 235959, memantine, SDZ 220-040, SDZ 220-581, synthaline, and their pharmaceutically acceptable salts.

It also relates to the use as mentioned above, characterized in that at least one of the molecules is Ifenprodil. It also relates to the use as mentioned above, characterized in that at least one of the molecules is cyproheptadine.

It also relates to the use as mentioned above, characterized in that the molecules are administered at a daily dose of between 0.1 mg and 1000 mg per day.

It also relates to a pharmaceutical composition comprising at least two molecules chosen from the group of molecules having a simultaneous antagonistic action on the alphal-noradrenergic, glutamatergic NMDA and serotoninergic 5HT2 receptors constituted by the following molecules:

1- (1-naphthyl) piperazine, séganserine, olanzapine, sarprogelate, mirtazapine, aripiprazole, mepiprazole, 4- (4-fluorobenzoyl) -1- (4-phenylbutyl) piperidine, AMI-193, amperozide, cinanserine, clozapine, cyclobenzaprine , ketanserin, MDL 11.939, mettergoline, methiothepine, methysergide, mianserin, N-desmethylclozapine, piperazine, pirenperone, ritanserin, RS 102221, sertindole, SB 200646, SB 204741, SDZ SER 082, spiperone, HA 11110, amosulalol, corynanthine, HEAT, Naftopidil, niguldipine, bunazosin, dapiprazole, prazosin, tamsulosin, RS 100329, RS 17053, terazosin, WB 4101, urapidil, 5-methylurapidil, (-) - MK801, (+) -MK801, (+/-) - 1- ( 1,2 diphenylethyl) piperidine, (2R, 3S) -Chlorpheg, (R) -4-carboxyphenyglycine, (R) -CPP, (RS) -CPP, arcane, CGP 37849, CGP 39551, CGS 19755, D-AP5, D-AP7, DL-AP5, DL-AP7, L-AP5, loperamide, LY 235959, memantine, SDZ 220-040, SDZ 220-581, synthaline, and their salts pharmacologically acceptable, associated with a pharmaceutically acceptable carrier or excipient.

It also relates to a pharmaceutical composition characterized in that the content of the molecule in the composition is between 0.1 mg and 1000 mg.

It also relates to a pharmaceutical composition characterized in that the associated molecules are Ifenprodil and Cyproheptadine.

Experimental results ;

Among the molecules tested, the results obtained with ifenprodil and cyproheptadine are presented below.

Reminder on the molecules:

Cyproheptadine: Periactin ^®

Symptomatic treatment of various allergic manifestations, 4 to 20 mg / day. Antihistaminic and antiserotoninergic activity.

Cyproheptadine was selected for its antiserotoninergic activity, particularly for its affinity for 5HT2 and 5HT1C receptors.

Ifenprodil: Vadilex ^® Treatment of painful manifestations of arteriopathies in ischemic thrust, neuroprotective agent. 5 to 15 mg / day.

Ifenprodil has been selected for its antagonistic properties with respect to NMDA and alphal-noradrenergic receptors. the

These two molecules are therefore particularly well described and pharmacological data in animals are available. We will remember those that are directly related to our field of study:

Cyproheptadine: no effect on locomotor activity at 2 mg / kg in mice (Semenova and Tiku, 1997, Costall et al., 1998). Cyproheptadine antagonizes the hyperlocomotor effect of opiates (Gurtu, 1990). Ifenprodil has anxiolytic effects (Fraser et al., 1996). Ifenprodil reduces the stimulating effects of alcohol, but does not block the expression of sensitization (Broadbent 2003). Ifenprodil reduces the physical signs induced by alcohol withdrawal (Malinowska et al., 1999).

In isolation, under certain experimental conditions, these two molecules reduce the acute locomotor effects of addictive substances without having any obvious effect on the development of sensitization after repeated administration.

The results obtained with these two molecules in isolation on locomotor hyperactivity induced by amphetamine and then in combination on the development of the sensitization induced after repeated administrations are set out below.

This example, described more precisely below, is not limiting. The other molecules making it possible to obtain similar results are chosen from the group consisting of the following molecules: the the the

1- (1-naphthyl) piperazine, séganserine, olanzapine, sarprogelate, mirtazapine, aripiprazole, mepiprazole, 4-

(Four-fluorobenzoyl) -1- (4-phenylbutyl) piperidine, AMI-193, amperozide, cinanserin, clozapine, cyclobenzaprine, ketanserin, MDL 11.939, metergoline, methiothepin, methysergide, rαiansérine, N-desmethylclozapine, piperazine, pirenp ^'Érone, ritanserin, RS 102221, sertindole, SB 200646, SB 204741, SDZ SER 082, spiperone,

AH 11110, amosulalol, corynanthine, HEAT, naftopidil, niguldipine, bunazosin, dapiprazole, prazosin, tamsulosin, RS 100329, RS 17053, terazosin, WB 4101, urapidil, 5-methylurapidil, (-) - MK801, (+) - MK801, (+/-) - 1- (1,2 diphenylethyl) piperidine, (2R, 3S) -Chlorpheg, (R) -4-carboxyphenyglycine, (R) -CPP, (RS) -CPP, arcane, CGP 37849, CGP 39551, CGS 19755, D-AP5, D-AP7, DL-AP5, DL-AP7, L-AP5, loperamide, LY 235959, memantine, SDZ 220-040, SDZ 220-581, synthaline, and their salts.

Example 1 Hardware

The principle of the behavioral sensitization test is based on the measurement of locomotor activity. This is measured in the open-field test.

The open-field motor and exploratory activity test The animals used are male C57 / BL6J mice aged 9 weeks at the beginning of the experiment.

The open-fields used to measure the activity are 4 square plexiglas transparent enclosures. Each open field is placed in a frame equipped with photocells to record animal movements. the

Effects of products on locomotor activity The products used have known psychotropic properties. At certain doses they can induce hypolocomotor effects. Since the principle of the study is based on the measurement of locomotor activity, it is preferable to have a preliminary evaluation of these effects in the experimental conditions used. The first step of the protocol consisted of measuring the effects of the products on the locomotor activity, in order to establish a range of doses that do not lead to a major incapacitating effect. Products: All products are dissolved in physiological saline (0.9% NaCl) so that the injection volume is 10 ml / kg of body weight.

IFENPRODIL was tested at the following doses: 1 mg / kg; 3 ^m g / kg and 10mg / kg. CYPROHEPTADINE was tested at the following doses: 0.3 mg / kg; 1 mg / kg; 3 mg / kg and 10 mg / kg. Summary of locomotor activity results: Ifenprodil alone has no significant effect on locomotion at doses below 10 mg / kg. Cyproheptadine alone begins to have a significant effect at doses greater than 3 mg / kg. results indicate that it is better not to use higher doses in the following experiments. Experiments were also conducted to evaluate the effect of the combination of products: IFENPRODIL (3 mg / kg) + CYPROHEPTADINE (1 mg / kg): decrease

IFENPRODIL (3 mg / kg) + CYPROHEPTADINE (0.3 mg / kg): decrease IFENPRODIL (I mg / kg) + CYPROHEPTADINE (0.1 mg / kg): no effect

IFENPRODIL (0.3 mg / kg) + CYPROHEPTADINE (0.3 mg / kg): no effect

In the amphetamine sensitization protocol, the doses used for the combination of products were chosen based on these first observations and then optimized during the protocol. IFENPRODIL (0.3 mg / kg) + CYPROHEPTADINE (0.3 mg / kg) IFENPRODIL (1 mg / kg) + CYPROHEPTADINE (1 mg / kg) IFENPRODIL (3 mg / kg) + CYPROHEPTADINE (1 mg / kg)

Behavioral awareness protocol

During this protocol, the animals are treated with amphetamine. Groups receive an administration of one of the products or a combination of both.

Protocol

Each passage takes place as follows:

- t = 0: put in the open-field

- t = 15 min: the injection ^period (NaCl, ifenprodil,

CYPROHEPTADINE or IFENPRODIL + CYPROHEPTADINE)

- t = 30 min: 2, ^e m ^m e ^e injection (NaCl or amphetamine)

- t = 90 min: exit of the open-field the

During the session the ^era, the animals receive NaCl at

: St and 2 ^nd injection. The experiment takes place over several sessions, spaced from 2 to 10 days.

The experiments are conducted on 5 groups of animals that received the following treatments at each session. Doses are shown in Figures 1, 2 and 3.

Results

Figure 1: Effect of treatment with ifenprodil and cyproheptadine on amphetamine-induced sensitization (n = 4 animals per group)

Sessions 2 and 3: ifenprodil 1 mg / kg and cyproheptadine 1 mg / kg

Following sessions: ifenprodil 3 mg / kg and cyproheptadine

1 mg / kg

On the ordinate: distance in cm (mean ± ESM) Figure 2: Effect of treatment with the combination of ifenprodil + cyproheptadine on amphetamine-induced sensitization (n = 4 animals per group)

Sessions 2 and 3: ifenprodil 1 mg / kg and cyproheptadine 1 mg / kg

Following sessions: ifenprodil 3 mg / kg and cyproheptadine

1 mg / kg

On the ordinate: distance in cm (mean ± E.S.M.)

Summary table

Effect on locomotor activity (cm traveled, mean ± SDS) of treatments alone and in combination at the first and last sensitization sessions.

(*) P <0.05, significantly different from the amphetamine group. the

Figure 3: Effect of treatment with the combination of ifenprodil + cyproheptadine in and out of amphetamine administrations (n = 4 animals per group) Session 2 to 4: Ifenprodil 0.3 mg / kg + cyproheptadine 0.3 mg / kg

Sessions 5 to 8: Ifenprodil 1 mg / kg + cyproheptadine 1 mg / kg

Sessions 9 to 12: Ifenprodil 0 mg / kg + cyproheptadine 0 mg / kg. The control group receives amphetamine as the other two groups.

On the ordinate: distance in cm (mean ± E.S.M.)

Conclusion

At the doses used, the products injected alone or in combination have no significant effect on amphetamine-induced hyperactivity.

Ifenprodil and cyproheptadine administered separately have limited effects on the development and expression of behavioral sensitization to amphetamine. The effect of ifenprodil is undoubtedly related to its antagonistic properties vis-à-vis both alphal-adrenergic and glutamatergic NMDA-type receptors. The effect of cyproheptadine is undoubtedly related to its antagonistic properties with respect to serotonergic receptors, in particular of the 5HT2 type. These effects are not durable, they disappear after repeated treatment. Ifenprodil and cyproheptadine administered in combination significantly reduce the development of sensitization (p <0.05). It is the non-selective and simultaneous blocking of alpha-noradrenergic, NMDA-glutamatergic and 5HT2-receptors. serotoninergic which is undoubtedly at the origin of this action.

Figure 3 shows that when the treatment is stopped, the response to amphetamine is identical to that of the controls. The combination of products has therefore reduced awareness; it has not only antagonized the locomotor effect of amphetamine.

These experiments show that ifenprodil and cyproheptadine are administered in combination at doses that have no major incapacitating effect and can significantly reduce the sensitization induced by psychostimulants. These results indicate that this combination of products can counteract the reinforcing effects of the different addictive substances, and consequently reduce the states of dependence.

Studies with other addictive substances (opiates, alcohol ...) show interesting results. They are used to evaluate the effectiveness of the use according to the invention of molecules alone or in combination with other experimental models of addiction such as free consumption and space preference. On the other hand, the effectiveness of the use according to the invention of molecules alone or in combination on noradrenergic, glutamatergic and serotonergic neutradmission systems, as well as its effects on psychostimulants, make this combination of this type of molecule , original and interesting antipsychotic substances. Example 2

By the use according to the invention of molecules alone or in combination has been demonstrated a true effect in vivo for relatively variable levels which may be between 0.1 mg and 1000 mg in pharmaceutical compositions. These values are in agreement with the known effective doses of each of the drugs taken alone. The modes of administration and the galenic also correspond to conventional modes of administration known to those skilled in the art.

This use according to the invention of molecules alone or in combination makes it possible to formulate new medicinal products intended to treat or prevent pathologies of the central nervous system, in particular pharmaco-addictions, psychoses, smoking, alcohol-related disorders. , schizophrenia, acute and chronic psychotic states, dementia, mood disorders, attention disorders, sleep disorders, impulsivity disorders, hyperactivity, acute and chronic psychotic states addictive addictions, alcohol dependence, psychostimulant addiction, opioid dependence, benzodiazepine dependence, gambling disorders, tobacco addiction.

Example 3

Given the pharmacological profile of the molecules chosen for noradrenergic and serotonergic receptors, antipsychotic activity was sought. The substances were tested in the model the

of locomotor hyperactivity induced by MK801. This model is particularly sensitive to atypical antipsychotics that have a good affinity for serotonergic and noradrenergic receptors. In this model and in our experimental conditions, clozapine (Img / kg) reduces MK 801-induced hyperactivity by 56%. Clozapine is an atypical neuroleptic of reference, which has a very good affinity for serotoninergic 5HT2 and noradrenergic alpha .

The molecules chosen according to the invention have demonstrated a real effect at the active doses in the preceding experiments (lmg / kg ifenprodil + lmg / kg cyproheptadine).

Effect of the combination lmg / kg ifenprodil + lmg / kg cyproheptadine on the MK801-induced locomotor activity (cm, mean ± E.S.M.) •

(*) P <0.05, significantly different from the MK 801 group. (N = 6 animals per group)

The combination of ifenprodil + cyproheptadine at effective doses in the addiction model antagonizes at 45% the hyperactivity induced by MK801.

Claims

the CLAIMS

1. Use of a molecule alone or in a combination selected from the group of molecules having a simultaneous antagonistic action on the alphal-noradrenergic receptors, glutamatergic NMDA and serotoninergic 5HT2, for the preparation of a medicament for treating the pathologies of the system central nervous system.

2. Use according to claim 1, characterized in that the pathologies are selected from pharmaco-dependence, psychosis, smoking, disorders related to alcohol consumption, schizophrenia, acute and chronic psychotic states, dementia , mood disorders, attention disorders, sleep disorders, impulsivity disorders, hyperactivity, acute and chronic psychotic states, states of addiction addiction, alcohol dependence , addiction to psychostimulants, opioid dependence, benzodiazepine addiction, tobacco addiction, gambling addiction.

3. Use according to any one of the preceding claims, characterized in that the group of molecules having a simultaneous antagonistic action on the alphal-noradrenergic receptors, NMDA glutamatergic and 5HT2 serotoninergic is constituted by the following molecules:

1- (1-naphthyl) -piperazine, ségansérine, olanzapine, ^{'sarprogelate,} mirtazapine, aripiprazole, mépiprazole, 4- the

(4-Fluorobenzoyl) -1- (4-phenylbutyl) piperidine, AMI-193, amperozide, cinanserine, clozapine, cyclobenzaprine, ketanserin, MDL 11.939, metergoline, methiothepine, methysergide, mianserine, N-desmethylclozapine, piperazine, pirenperone, ritanserin, RS 102221, sertindole, SB 200646, SB 204741, SDZ SER 082, spiperone, HA 11110, amosulalol, corynanthine, HEAT, naftopidil, niguldipine, bunazosin, dapiprazole, prazosin, tamsulosin, RS 100329, RS 17053, terazosin, WB 4101, urapidil , 5-methylurapidil, (-) - MK801, (+) - MK801, (+/-) - 1- (1,2-diphenylethyl) piperidine, (2R, 3S) -Chlorpheg, (R) -4-carboxyphenylglycine, ( R) -CPP, (RS) -CPP, arcane, CGP 37849, CGP 39551, CGS 19755, D-AP5, D-AP7, DL-AP5, DL-AP7, L-AP5, loperamide, LY 235959, memantine, SDZ 220-040, SDZ 220-581, synthaline, and their pharmaceutically acceptable salts.

4. Use according to any one of the preceding claims, characterized in that at least one of the molecules is Ifenprodil.

5. Use according to any one of the preceding claims, characterized in that at least one of the molecules is cyproheptadine.

6. Use according to any one of the preceding revendiations, characterized in that the molecules are administered at a daily dose of between 0.1 mg and 1000 mg per day.

7. A pharmaceutical composition comprising at least two molecules chosen from the group of molecules having a simultaneous antagonistic action on the alphal- noradrenergic, glutamatergic NMDA and 5HT2 serotoninergic consisting of the following molecules: 1- (1-naphthyl) -piperazine, séganserine, olanzapine, sarprogelate, mirtazapine, aripiprazole, mepiprazole, 4- (4-fluorobenzoyl) -1- (4-phenylbutyl) piperidine, AMI-193, amperozide, cinanserin, clozapine, cyclobenzaprine, ketansetrine, MDL 11.939, metergoline, methiothepine, methysergide, mianserin, N-desmethylclozapine, piperazine, pirenperone, ritanserin, RS 102221, sertindole, SB 200646, SB 204741, SDZ SER 082, spiperone, AH 11110, amosulalol, corynanthine, HEAT, naftopidil, niguldipine, bunazosin, dapiprazole, prazosin, tamsulosin, RS 100329, RS 17053, terazosin, WB 4101, urapidil, 5-methylurapidil, (-) - MK801, (+ ) -MK801, (+/-) - 1- (1,2 diphenylethyl) piperidine, (2R, 3S) -Chlorpheg, (R) -4-carboxyphenyglycine, (R) -CPP, (RS) -CPP, arcane, CGP 37849, CGP 39551, CGS 19755, D-AP5, D-AP7, DL-AP5, DL-AP7, L-AP5, loperamide, LY 235959, memantine, SDZ 220-040, SDZ 22 0-581, synthaline, and their pharmaceutically acceptable salts, associated with a pharmaceutically acceptable carrier or excipient.

8. Pharmaceutical composition according to claim 7, characterized in that the content of the molecule in the composition is between 0.1 mg and 1000 mg.

9. Pharmaceutical composition according to any one of claims 7 to 8, characterized in that the associated molecules are Ifenprodil and cyproheptadine.