WO1997004797A1

WO1997004797A1 - Use of neuronal calcium channel blockers for the manufacture of a medicament for the treatment of psychoses, schizophrenia and cocaine or amphetamine addiction

Info

Publication number: WO1997004797A1
Application number: PCT/US1996/011365
Authority: WO
Inventors: Thomas Gary Heffner; Michael Francis Rafferty; James Nicholson Wiley
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1995-07-26
Filing date: 1996-07-08
Publication date: 1997-02-13
Anticipated expiration: 1998-01-26
Also published as: AU6454096A

Abstract

Neuronal calcium channel blockers: φ-conotoxin MV11a, φ-conotoxin GV1a, and φ-conotoxin TV1a are useful in the treatment of acute psychotic episode resulting from a psychiatric disorder or from cocaine or amphetamine toxicity.

Description

NEURONAL CALCIUM CHANNEL BLOCKERS FOR THE MANUFACTURE OF A MEDICAMENT E TREATMENT OF PSYCHOSES, SCHIZOPHRENIA AND COCAINE OR AMPHETAMINE

ADDICTION

BACKGROUND OF THE INVENTION

It is widely believed that the pathogenesis of schizophrenia and related psychotic disorders is the excessive activity of specific dopamine-utilizing neurons within the central nervous system (Neumeyer J.L., in "Principles of Medicinal Chemistry," Foye .O., ed. , Lea & Febiger, 1989:189-211). Evidence in support of this hypothesis has been the successful therapeutic application of specific dopamine receptor antagonists, now commonly called neuroleptics, for the treatment of these disorders. However, clinical experience has demonstrated that chronic use of neuroleptic agents in patients can result in debilitating motor disturbances, which in some cases are not reversible (Baldessarini R.J., in "Goodman and Gilman's The Pharmacological Basis of Therapeutics," 8th edition, A. Goodman Gilman, ed. , Pergamon Press, 1990:383-402) .

Release of neurotransmitters from neurons is generally found to be dependent upon an influx of calcium ions into the presynaptic ending. This influx is dependent upon calcium ion-specific channels on the membrane surface which become activated as a result of depolarization of the neuronal membrane, and so are generally referred to as voltage-activated calcium channels (VACC) . It is now known that several distinct VACCs exist, and that certain of these subtypes are associated specifically with neurons (Ramachandran J., et al. , in "Perspectives in Medicinal Chemistry," Testa B., et al. , eds., Verlag Helvetica Chimica Acta, 1993:374-388). A family of peptides have been isolated from the venom of fish-eating marine snails of the genus Conus which potently and specifically antagonize the so-called N-type VACC. When applied to CNS neuronal preparations, these toxins have been found to inhibit the evoked release of catecholamines such as norepinephrine and dopamine (Olivera, et al. , Annual Review of Biochemistry, 1994;63:823-867). Given that schizophrenia is a manifestation of excessive release of dopamine from neurons, it was reasoned that application of a compound which would specifically inhibit the release of this neurotransmitter would result in therapeutic benefit.

Certain pharmacological agents, notably amphetamine and cocaine, which have been reported to produce psychotic states in man, have also been found to enhance dopamine neurotransmission within the CNS (Evenden J.L. and Ryan C.N., in "Psychotropic Drugs of Abuse," Balfour D.J.K., ed. , Pergamon Press, 1990:1-21). In non-human species, administration of amphetamine and cocaine has been demonstrated to induce well-characterized behaviors which can be prevented or reversed by the administration of neuroleptics . For example, amphetamine and cocaine are potent stimulants in rodents, resulting in a well-characterized increase in spontaneous locomotor activity (Kline E.J., et al. , Journal of Pharmacology and Experimental Therapeutics, 1992;260:1174-1179). Amphetamine-induced behaviors have therefore become a commonly used preclinical screen for drugs to treat schizophrenia and related psychoses.

Cocaine is a potent and specific blocker of the reuptake of dopamine by neurons . Dopamine reuptake is an important mechanism for the termination of dopamine- dependent synaptic neurotransmission. Therefore, the psychotomimetic and CNS stimulant effects of cocaine also appear to be a manifestation of increased dopamine neurotransmission (Evenden J.L. and Ryan C.N., ibid. ) . The instant invention is the administration of a specific Conus venom constituent which blocks N-type VACCs and can suppress the behavioral actions of amphetamine or cocaine at doses which when administered alone do not alter normal behavior in animals . These results show that blockade of N-type VACCs will be a useful mechanism for the treatment of schizophrenia and stimulant-induced psychoses.

In Yamada K., et al. , Neuroscience Letters, 1994;165:191-194, it was reported that ω-conotoxin GVla inhibited ethylphenidate-induced behavioral stimulation in the locomotor activity paradigm. However, the authors report that methamphetamine- induced stimulation was not inhibited, which teaches against the findings described in the instant invention. Popoli P., et al. , Life Sciences, 1993;52:2055-2061, reported that ω-conotoxin attenuated the ataxia and stereotypic behaviors induced by phencyclidine (PCP) . However, this result is also inconsistent with the results reported in the instant invention.

SUMMARY OF THE INVENTION

The instant invention is to the use of compounds which block calcium influx through neuronal voltage- activated calcium channels to treat schizophrenia and related psychiatric diseases, to treat psychotic episodes induced by cocaine or other related drugs of abuse, and to treat acute psychotic episodes resulting from amphetamine toxicity. The preferred compounds useful in the exercise of the instant invention are ω-conotoxin MVlla, ω-conotoxin GVla, and ω-conotoxin TVla (SNX-185) (Fox J.A. , Heuroflclence Letters , 1994;165:157-160).

The compounds may be useful as an acute therapy for psychotic episodes by parenteral administration.

The preferred compounds are the first with this mechanism found suitable for the treatment of psychosis and the emergency treatment of cocaine- or amphetamine- induced psychotic episodes by parenteral injection.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates the time in minutes of the effect of SNX-185 on spontaneous locomotor activity in mice.

Figure 2 illustrates the effect of amphetamine treatment on the level of spontaneous locomotor activity in mice, and the ability of the antipsychotic agent haloperidol to block the actions of amphetamine in mice.

Figure 3 illustrates the effect of SNX-185 at various doses on the behavioral effects of amphetamine in mice.

Figure 4 illustrates the effect of SNX-185 on the stimulant properties of cocaine in mice.

DETAILED DESCRIPTION

The compounds of the invention were tested for their ability to inhibit locomotor activity in mice either as a measure of normal behaviors or following administration of a CNS stimulant as a measure of antipsychotic activity according to the assay described in McLean J.R., et al. , Pharmacology, Biochemistry, and Behavior, 1978;8:97-99. CNS stimulants employed in the characterization of the compounds identified in this invention include amphetamine and cocaine. The ability of compounds of the invention to block apomorphine- induced climbing was evaluated using the method of Constentin J., et al. , Psychopharmacology, 1976;50:1-6. The ability of the compounds to attenuate mescaline- induced scratching was evaluated using the method of Fellows E.J. and Cook L., in "Psychotropic Drugs," Garrattivi S. and Ghatti V. , eds., Elsevier (Amsterdam), 1957:397-404.

Phencyclidine (PCP) -induced ataxia was measured and apomorphine using the following procedure. Male Swiss-Webster mice weighting 20 to 30 g were treated with test compounds, followed after 10 minutes by an intraperitoneal injection of PCP (4 mg/kg) . Fifteen minutes later, animals were placed on an inverted screen and evaluated for their ability to remain on the screen. At this dose of PCP, typically 60% to 100% of the animals fail this test. A dose-response determination is carried out for those compounds which display an ability at an initial test dose to attenuate the ataxic effects of PCP.

The data obtained for ω-conotoxin TVla (SNX-185) are summarized in Table 1 below.

TABLE 1 Test Results for ω-conotoxin TVla (SNX-185) in Mice mTes_Jt. _TP,roced .iure EDcn Value (,i?c^υv ng,)

Spontaneous Locomotor Activity 64.8 Amphetamine-Stimulated Activity 8.9

Cocaine-Stimulated Activity 10

Phencyclidine Ataxia >30

Apomorphine Climbing >30

Mescaline-Induced Scratching >30 Antiwrithing 8.8

CNS Tremors @ 60

Table 1 summarizes the data for these and other experiments . A lack of effect on the behavioral properties of phencyclidine or mescaline is evidence for pharmacological specificity by ω-conotoxin TVla toward dopamine-dependent behaviors. Also, the lack of effect on apomorphine-induced behaviors is evidence for an effect of ω-conotoxin TVla on dopamine release, rather than on the actions of dopamine at postsynaptic receptors. The lack of effect by ω-conotoxin TVla in this last experiment clearly distinguishes it from haloperidol, which potently blocks the effects of apomorphine.

Based on this behavioral profile, it is clear that ω-conotoxin TVla can suppress evoked release of dopamine within the CNS by the blockade of N-type VACCs localized to presynaptic nerve endings . The ability to reverse the actions of stimulants which act by enhancing dopamine neurotransmission is a property which is shared with known antipsychotic agents such as haloperidol. Therefore, these results show that parenteral administration of specific blockers of N-type VACCs will be useful for the treatment of psychosis, including the acute psychotic episodes induced by drugs of abuse. Evidence that this mechanism will confer therapeutic advantages over haloperidol and other neuroleptics is found in the fact that ω-conotoxin TVla can suppress dopamine-dependent evoked behaviors at doses which alone do not alter normal behavior. In contrast, the doses of haloperidol required to suppress amphetamine-induced stimulation also suppress basal behavior.

Figure 1 shows the effect of SNX-185 on the spontaneous (basal) level of exploratory activity by mice in a locomotor activity chamber. Mice (N = 21-27) were injected with compound 10 minutes prior to the beginning of the experiment. The results illustrate that SNX-185 can dose-dependently suppress basal behavior after intraventricular administration. The dose which produced 50% of the maximum achievable effect (ED₅₀ value) was calculated to be 64.8 ng. Figure 2 shows the inhibitory effect of haloperidol, which is a potent dopamine receptor blocker and widely used antipsychotic agent on the stimulant property of amphetamine in the locomotor activity chamber. The ED^_Q dose of haloperidol given intraperitoneally was calculated to be 0.02 mg/kg.

Figure 3 shows the ability of ω-conotoxin TVla to reverse amphetamine-induced stimulation in this same paradigm. The ED^_Q value in this experiment was 8.9 ng, which is well below the dose required to alter normal behavioral activity. This experiment demonstrated a common behavioral profile for ω-conotoxin TVla with a known antipsychotic drug in a model which has been used for purposes of predicting clinically useful antipsychotic activity. Figure 4 shows the ability of ω-conotoxin TVla to reverse the stimulant effects of cocaine in mice. The ED₅₀ value for ω-conotoxin TVla administered intraventricularly in this experiment was calculated to be approximately 10 ng.

The compounds of the present invention can be prepared and administered in a wide variety of parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I .

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

The powders preferably contain from five or ten percent to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with appropriate material as a carrier. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation.

The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

In therapeutic use as schizophrenic agents, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 1 mg to about 50 mg per kilogram daily. A daily dose range of about 5 mg to about 25 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The compounds of the invention are preferably formulated for parenteral administration, for example, in emergency situations in a suitable inert carrier such as a sterile physiological saline solution. The concentration of the compound in the carrier is about 0.1-10 mg/mL. However, the dose administered will be determined by the route of administration and as determined by a skilled physician.

Claims

1. A method of antagonizing activity at neuronal-type calcium channels to suppress the behavioral effects of amphetamine or cocaine, which comprises administering a compound with said activity to a patient in need of said treatment.

2. A method of treating schizophrenia by administration of a compound with antagonist activity at neuronal-type calcium channels, which comprises administering said compound to a patient in need of said treatment in unit dosage form.

3. A method of treating an acute psychotic episode comprising administering a compound with antagonist activity of neuronal-type calcium channels, which comprises administering said compound to a patient in need of said treatment in unit dosage form.

4. A method according to Claims 1 through 4 wherein the compound is selected from ω-conotoxin MVlla, ω-conotoxin GVla, and ω-conotoxin TVla.

5. A method according to Claim 1 wherein the compound is administered parenterally.

6. A pharmaceutical composition effective in treating a mammal suffering from schizophrenia, an acute psychotic episode resulting from a psychiatric disorder, from cocaine use or from amphetamine toxicity, comprising a compound with antagonist activity at neuronal-type calcium channels, and pharmaceutically acceptable carrier in unit dosage form.

7. A composition according to Claim 7 with the compound selected from ω-conotoxin MVlla, ω-conotoxin GVla, and ω-conotoxin TVla.