阅读说明：本技术 治疗与神经损伤相关的精神障碍和疼痛的药物组合物和用途 (Pharmaceutical composition and use for treating mental disorders and pain associated with nerve damage ) 是由 贺菊方 张绪 冯鹤敏 张鸽 徐声辉 侯舒容 于 2020-04-26 设计创作，主要内容包括：胆囊收缩素-2受体拮抗剂或其药学上可接受的盐在制备用于治疗精神障碍或与神经损伤有关的疼痛的药物中的用途。药物组合物,该药物组合物包含胆囊收缩素-2受体拮抗剂或其药学上可接受的盐作为活性成分、一种或多种抗抑郁化合物,和药学上可接受的赋形剂。(Use of a cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a psychiatric disorder or pain associated with neurological damage. A pharmaceutical composition comprising a cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof as active ingredient, one or more antidepressant compounds and a pharmaceutically acceptable excipient.)

1. Use of a cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a psychotic disorder.

2. The use according to claim 1, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (Ia):

Wherein R is₁And R₂Independently a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₅Alkyl, substituted or unsubstituted arylOr heteroaryl; and

R₃is a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₃Alkyl, or C₁To C₃An alkylamino group.

3. The use according to claim 2, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (Ia) and R₁Is straight-chain or branched C₁To C₄An alkyl group, or a substituted or unsubstituted aryl group; r₂Is substituted or unsubstituted aryl, or heteroaryl; and R₃Is methyl, ethyl, methylamino or ethylamino.

4. The use according to claim 1, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (IIa) or formula (IIIa):

5. the use of claim 1, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (IIb) or formula (IIIb):

6. the use according to claim 1, wherein the psychiatric disorder is depression.

7. The use according to claim 1, wherein the cholecystokinin-2 receptor antagonist is administered to the subject in combination with one or more antidepressant compounds.

8. The use according to claim 7, wherein the antidepressant compound is selected from the group consisting of: citalopram, escitalopram, paroxetine, fluoxetine, sertraline, selegiline, isocarboxazid, tranylcypromine, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, trazodone, nefazodone, mirtazapine, bupropion, venlafaxine, duloxetine, and desvenlafaxine.

9. Use according to claim 7, wherein the cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof is formulated for administration via injection.

10. Use of a cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain associated with nerve damage.

11. The use according to claim 10, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (Ia):

wherein R is₁And R₂Independently a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₅An alkyl, substituted or unsubstituted aryl, or heteroaryl group; and

R₃is a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₃Alkyl, or C₁To C₃An alkylamino group.

12. The use according to claim 11, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (Ia) and R₁Is straight-chain or branched C₁To C₄An alkyl group, or a substituted or unsubstituted aryl group; r₂Is substituted or unsubstituted aryl, or heteroaryl; and R₃Is methyl, ethyl, methylamino or ethylamino.

13. The use according to claim 10, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (IIa) or formula (IIIa):

14. The use of claim 10, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (IIb) or formula (IIIb):

15. the use of claim 10, wherein the pain associated with nerve damage is chronic pain.

16. A pharmaceutical composition comprising as active ingredients a cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof, one or more antidepressant compounds and optionally a pharmaceutically acceptable excipient.

17. The pharmaceutical composition according to claim 16, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (Ia):

wherein R is₁And R₂Independently a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₅An alkyl, substituted or unsubstituted aryl, or heteroaryl group; and

R₃is a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₃Alkyl, or C₁To C₃An alkylamino group.

18. The pharmaceutical composition of claim 16, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (Ia) and R₁Is straight-chain or branched C₁To C₄An alkyl group, or a substituted or unsubstituted aryl group; r₂Is substituted or unsubstituted aryl, or heteroaryl; and R ₃Is methyl, ethyl, methylamino or ethylamino.

19. The pharmaceutical composition of claim 16, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (IIa) or formula (IIIa):

20. the pharmaceutical composition of claim 16, wherein the cholecystokinin-2 receptor antagonist has the structure of formula (IIb) or formula (IIIb):

21. the pharmaceutical composition according to claim 16, wherein the antidepressant compound is selected from the group consisting of: citalopram, escitalopram, paroxetine, fluoxetine, sertraline, selegiline, isocarboxazid, tranylcypromine, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, trazodone, nefazodone, mirtazapine, bupropion, venlafaxine, duloxetine, and desvenlafaxine.

Technical Field

The present invention relates to a method of treating a psychotic disorder, in particular depression, in a subject by administering a cholecystokinin (CCK) receptor antagonist to the subject, particularly but not exclusively. The invention also relates to methods of treating pain associated with nerve injury in a subject by administering a cholecystokinin (CCK) receptor antagonist to the subject. The invention also relates to pharmaceutical compositions for use in the methods and the use of cholecystokinin (CCK) receptor antagonists for the preparation of a medicament for the treatment of psychiatric disorders or pain associated with neurological damage.

Background

Psychiatric disorders include a variety of neuropsychiatric disorders. Depression is a mental disorder which refers to mental health problems characterized by a lack of positive effects, such as loss of interest and enjoyment in the daily pursuit, loss of enjoyment and experience that would normally be enjoyed. Depression may also be characterized by a depressed mood and a series of associated emotional, cognitive, physical and behavioral symptoms. Major depression may be experienced in 4-10% of the life of the world, and persistent depression (low-grade chronic depressive symptoms) may be encountered in about 2.5-5% of the world, with values varying due to geographical differences and differences in the method of assessment (waracich et al, 2004).

Antidepressants currently available on the market can be divided into Selective Serotonin Reuptake Inhibitors (SSRIs), monoamine oxidase inhibitors (MAOI), tricyclic antidepressants, atypical antidepressants, and selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), with SSRIs being most common and widely used. However, the use of SSRIs can cause some common side effects including nausea, tremor, nervousness, insomnia and sexual problems. Therefore, there is still a strong need for new and effective methods for treating psychiatric disorders such as depression.

Disclosure of Invention

In the present invention, the inventors have unexpectedly found that antagonists of the cholecystokinin-2 (CCK 2) receptor are useful in the treatment of psychiatric disorders and pain associated with nerve injury. And as Neuroscience Letter, 1981, 24 (2): 175-180, the present inventors have found that inhibition of the CCK2 receptor is effective in treating the major and minor signs of depression and reducing pain.

In a first aspect, the present invention provides the use of a cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a psychotic disorder.

The CCK2 receptor antagonist according to the present invention has the structure of formula (Ia), including any pharmaceutically acceptable salts thereof:

Wherein R is₁And R₂Independently a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₅An alkyl, substituted or unsubstituted aryl, or heteroaryl group; and R is₃Is a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₃Alkyl, or C₁To C₃An alkylamino group.

Specifically, the CCK2 receptor antagonist has a structure of formula (Ia), and R₁Is straight-chain or branched C₁To C₄An alkyl group, or a substituted or unsubstituted aryl group; r₂Is substituted or unsubstituted aryl, or heteroaryl; and R₃Is methyl, ethyl, methylamino or ethylamino.

Preferably, the CCK2 receptor antagonist has the structure of formula (IIa) or formula (IIIa):

more preferably, the CCK2 receptor antagonist has the structure of formula (IIb) or formula (IIIb):

in one embodiment, a CCK2 receptor antagonist is administered to a subject in combination with one or more antidepressant compounds. In particular, the antidepressant compound is selected from the group consisting of: citalopram (citalopram), escitalopram (escitalopram), paroxetine (parooxetine), fluoxetine (fluoxetine), sertraline (sertraline), selegiline (selegiline), isocarboxazid (isocarboxazide), tranylcypromine (tranylcypromine), amitriptyline (amitriptyline), amoxapine (amoxapine), desipramine (desipramine), doxepin (doxepin), imipramine (imipramine), nortriptyline (nortriptyline), protriptyline (protriptyline), trimipramine (trimipramine), maprotiline (maprotiline), trazodone (trazodone), nefazodone (nefazodone), mirfazodone (mizazazapine), bupropion (bupropion), venlafaxine (doxazone), and nefavafloxacin (doxazone).

In one embodiment, the CCK2 receptor antagonist or a pharmaceutically acceptable salt thereof is formulated for administration via injection.

In a second aspect, the present invention provides the use of a cholecystokinin-2 receptor antagonist or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of pain associated with nerve damage. In particular, the pain is chronic pain.

In a third aspect, the present invention relates to a pharmaceutical composition comprising as active ingredients a CCK2 receptor antagonist as described above or a pharmaceutically acceptable salt thereof and one or more antidepressant compounds. Preferably, the antidepressant compound is selected from the group consisting of: citalopram, escitalopram, paroxetine, fluoxetine, sertraline, selegiline, isocarboxazid, tranylcypromine, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, trazodone, nefazodone, mirtazapine, bupropion, venlafaxine, duloxetine, and desvenlafaxine.

In particular, the inventors have found that benzodiazepines, i.e. compounds of formula (IIb) and formula (IIIb) (referred to as YM022 and YF476, respectively) can selectively inhibit the CCK2 receptor. These two compounds are generally used for the treatment and/or prevention of gastric and duodenal ulcers, gastritis, reflux esophagitis, Zollinger-ellison syndrome (Zollinger-ellisondyneme), osteoporosis, neuroendocrine tumors and digestive system tumors, but not for psychiatric disorders, in particular depression or pain. Experimental results of the present invention indicate that YM022 and YF476 may be effective in treating the major and minor signs/forms of depression and reducing pain.

In addition, these compounds were found to have a long half-life in vivo, providing antidepressant and analgesic effects. In particular, a single subcutaneous administration of these compounds can produce high circulating concentrations of the compounds in the body for up to 8 weeks, whereas current clinically required antidepressants need to be taken at least once a day for a similar purpose. Therefore, these compounds are considered to be effective in the treatment of psychiatric disorders and pain, and further useful in the development of drugs for the treatment of treatment-resistant depression and treatment-resistant pain.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The present invention includes all such variations and modifications. The invention also includes all of the steps and features referred to or indicated in the specification, individually or collectively, and any and all combinations of such steps or features.

Other features and aspects of the present invention will become apparent by consideration of the following detailed description and accompanying drawings.

Drawings

Figure 1A is a bar graph showing the effect of treatment with compound of formula (IIb) or compound of formula (IIIb) (YM 022 and YF476, respectively, 0.3 μ g/kg) on the time to immobility (seconds) of tail suspension experiments in SNI mice 40 days after sci branch selective injury (SNI) SNI surgery (i.e., 10 days after discontinuation of YM022 and YF 476), expressed as mean ± SEM). In the sham group, the sciatic nerve (sural nerve, common peroneal nerve, tibial nerve) was surgically found but not severed.

FIG. 1B is a bar graph showing the effect of compound YM022 or YF476 (0.3. mu.g/kg) treatment on body weight (grams) of SNI mice at 40 days post-SNI surgery (i.e., 10 days post-withdrawal of YM022 or YF 476) (expressed as mean. + -. SEM).

Fig. 2 is a line graph showing the effect of treatment with compound YM022 or YF476 on the SNI mouse mechanical threshold (grams) in the von frey cellosilk assay on the day before surgery (day-1), the day after injection of compound YM022 or YF476 (day 1), day 7 (day 7), or day 8 (day 8).

FIG. 3A is a bar graph showing the time of immobility (expressed as mean. + -. SEM) in acute tail suspension experiments for mice treated with saline, Compound YF476 (3. mu.g/kg or 30. mu.g/kg) or Compound YM022 (3. mu.g/kg or 30. mu.g/kg).

FIG. 3B is a bar graph showing the immobility time (expressed as mean. + -. SEM) in acute forced swim experiments for mice treated with saline, Compound YF476 (30. mu.g/kg) or Compound YM022 (30. mu.g/kg).

Detailed Description

Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, "comprising" means including the following elements, but not excluding others. By "consisting of" is meant that the material consists only of it, i.e. is formed from the respective elements. As used herein, the forms "a", "an" and "the" are intended to include both the singular and the plural, unless the context clearly indicates otherwise.

In a first aspect, the present invention provides a method of treating a subject suffering from a psychiatric disorder. The method comprises the step of administering to the subject an effective amount of a cholecystokinin-2 (CCK2) receptor antagonist. The term "CCK receptor antagonist" as used herein generally refers to a specific type of receptor antagonist of the CCK receptor site. In the art, two subtypes of receptors are known, namely the CCK1 receptor and the CCK2 receptor (also known as CCK a receptor and CCK B receptor). CCK receptor antagonists are defined by their selectivity for each receptor subtype, i.e., CCK1 receptor antagonist and CCK2 receptor antagonist.

The CCK2 receptor antagonists of the present invention may be modified peptidic or non-peptidic molecules.

In one embodiment, the CCK2 receptor antagonist has the structure of formula (Ia):

wherein R is₁And R₂Independently a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₅An alkyl, substituted or unsubstituted aryl, or heteroaryl group; and R is₃Is a hydrogen atom, a substituted or unsubstituted, linear or branched C₁To C₃Alkyl, or C₁To C₃An alkylamino group.

It has been found that CCK2 receptor antagonists having the following formula (Ia) or preferably the following formula (Ib) are particularly suitable for the treatment of psychotic disorders.

Wherein R is₁、R₂And R₃As defined above.

Specifically, R₁Is straight-chain or branched C₁-C₄An alkyl group such as methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, or an unsubstituted aryl group such as phenyl, or a substituted aryl group such as tolyl, xylyl, naphthyl, halophenyl, thiophenyl, or aminophenyl. R₂Is a substituted or unsubstituted aryl group as defined above, or a heteroaryl group such as pyridyl, pyrimidinyl, thienyl, imidazolyl-pyridyl or pyrazolyl. R₃Is methyl, ethyl, methylamino or ethylamino.

In a preferred embodiment, the CCK2 receptor antagonist has the structure of formula (IIa) or formula (IIIa):

including any pharmaceutically acceptable salt, solvate or anhydrate thereof, and including any stereoisomer, diastereomer, enantiomer or racemate thereof.

Specifically, the CCK2 receptor antagonist has the structure of formula (IIb) or formula (IIIb).

Including any pharmaceutically acceptable salts, solvates or anhydrates thereof. The compound of formula (IIb) is referred to as YM022, and the compound of formula (IIIb) is referred to as YF 476. These compounds may be prepared or obtained according to suitable methods.

IC of YM022 for CCK1 receptor ₅₀IC at 63nM for the CCK2 receptor₅₀It was 0.07 nM. IC of YF476 to CCK1 receptor₅₀0.5 μ M and IC for CCK2 receptor₅₀It was 0.11 nM. YM022 and YF476 have antagonistic actions on CCK1 and CCK2 receptors and selectively inhibit CCK2 receptors. The CCK2 receptor antagonists of the present invention exhibit stable and prolonged pharmacological effects. Advantageously, the CCK2 receptor antagonists of the present invention have an extended half-life in vivo and are useful as effective and long-lasting treatments of psychiatric disorders.

In alternative embodiments, the CCK2 receptor antagonist may be a molecule selected from the group consisting of: proglumde, CI-988, CI-1015, L-365260, L-369293, RP-69758, LY-255910, LY288513, PD-135158, PD-145942 and derivatives thereof.

The invention also contemplates any pharmaceutically acceptable salts, hydrates, solvates, anhydrates as well as enantiomers and mixtures, stereoisomeric forms, racemates, diastereomers and mixtures thereof of the CCK2 receptor antagonist of the invention.

The term "solvate" refers to a complex of variable stoichiometry formed by a solute, i.e., a CCK2 receptor antagonist, and a solvent. If the solvent is water, the solvate formed is a hydrate. As understood in the art, the term "anhydrate" as used herein refers to any compound that is free of bound water. Suitable pharmaceutically acceptable salts are those which are suitable for administration to a subject, particularly a mammal such as a human, and which can be prepared in sufficient purity and used in the preparation of a pharmaceutical composition. The terms stereoisomers, diastereomers, enantiomers and racemates are known to the skilled person.

"treating" a mental disorder includes, inter alia, any treatment of a mental disorder, including inhibiting, ameliorating, or alleviating symptoms, reducing the incidence of symptoms, or arresting the development of symptoms manifested directly or indirectly as a result of a mental disorder. Treating a psychiatric disorder may also include preventing the onset and/or development of the psychiatric disorder.

The term "psychiatric disorder" refers to a neuropsychiatric disorder in which the subject suffers from a single, combination or breadth of affective, cognitive, physical and/or behavioral symptoms. The term "psychiatric disorder" herein is not intended to imply a distinction between "physical" and "mental" disorders, but is to be construed to cover the full scope of these disorders. In the art, there are various psychiatric disorders including, but not limited to, neurodevelopmental disorders, psychotic disorders, bipolar disorder and related disorders, anxiety disorders, disorders associated with trauma and stress, mood disorders or depression. The mental disorder may include more than one neuropsychiatric disorder. In a preferred embodiment, the psychiatric disorder is a depressive disorder. In a most preferred embodiment, the psychiatric disorder is depression.

As discussed herein, depression refers to a broad range of mental health problems that negatively impact a subject's feeling, thought, or behavior, and may be characterized by a depressed mood or feeling of sadness, or loss of interest and enjoyment in the activities and experiences that were once enjoyed. Symptoms may include one or more of a loss of mood, loss of interest, altered appetite (including weight loss or weight gain), altered sleep patterns, lack of energy or increased fatigue, increased concentration or inability to make decisions or purposeless physical activity. The depression described herein incorporates various types of depression including, but not limited to, major depression, mood disorders, atypical depression, postpartum depression.

In one embodiment herein, administration of a CCK2 receptor antagonist to a subject can produce an alleviation effect on the depressive disorder of the subject, particularly a sustained, stable alleviation effect of depression in the subject.

The term "effective amount" generally means an amount sufficient to produce a therapeutically desirable result, wherein the exact nature of the result depends on the particular condition being treated. The CCK2 receptor antagonists of the present invention may be included in a composition, particularly a pharmaceutical composition, in an effective amount, i.e., an amount suitable for treating or preventing depression in a subject, particularly a mammal.

The subject may be a human or an animal, in particular the subject is a mammal, preferably a human. Thus, the subject is preferably a human suffering from a psychiatric disorder, in particular depression. The subject may also include persons who are resistant to conventional antidepressants, i.e., the subject may suffer from treatment-resistant depression.

An effective amount of a CCK2 receptor antagonist of the invention may depend on the species, weight, age, and individual condition of the subject, and may be determined by standard methods such as experimental animals. In embodiments where the subject is a mouse, the effective amount is preferably about 0.001mg/kg, 0.01mg/kg, 0.1mg/kg, 1mg/kg, 10mg/kg, 100mg/kg, or 500 mg/kg. An effective amount of a CCK2 receptor antagonist can be indicated by a reduction in the severity or incidence of depressive symptoms in a subject over a defined period of time.

The skilled artisan will appreciate that, based on susceptibility factors, a determination is made according to the present invention whether a subject is in need of treatment for a psychiatric disorder or treatment for depression. The term "susceptibility factor" refers to a factor or condition that predisposes a subject to a disease or disorder, i.e., a mental disorder or depression in the present disclosure. Susceptibility factors for mental disorders, particularly depression, may include, but are not limited to, family genetic factors; sleep disorders, such as chronic sleep problems; chronic diseases, such as chronic pain, arthritis, parkinson's disease, multiple sclerosis, cancer, etc., may be associated with a higher incidence of depression; drug abuse or certain drug treatments; or social factors such as abuse or lack of social support.

In embodiments, the CCK2 receptor antagonists of the present invention may be administered in combination with an effective amount of one or more antidepressant compounds. The term "antidepressant compound" includes drugs that are typically administered to subjects who are not resistant to current antidepressant drug therapies, i.e., compounds known to be useful in the treatment of depression.

In particular, the antidepressant compound is selected from the group consisting of: citalopram, escitalopram, paroxetine, fluoxetine, sertraline, selegiline, isocarboxazid, tranylcypromine, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, trazodone, nefazodone, mirtazapine, bupropion, venlafaxine, duloxetine, and desvenlafaxine.

The antidepressant compounds may be administered before, after or simultaneously with the CCK2 receptor antagonist, in particular before or simultaneously with the CCK2 receptor antagonist, further preferably simultaneously with the CCK2 receptor antagonist.

The CCK2 receptor antagonist according to the present invention may be administered to a subject by oral, injectable, rectal, topical, parenteral, transdermal or inhalation routes. In embodiments where the subject is a mouse, the CCK2 receptor antagonist is administered to the subject by injection. The term injection includes intraperitoneal, intravenous, intramuscular, subcutaneous and intradermal administration. In a preferred embodiment, the CCK2 receptor antagonist is administered to the subject by injection, preferably intravenous or subcutaneous injection. In this embodiment, the CCK2 receptor antagonist or a pharmaceutically acceptable salt thereof is formulated for administration via injection.

In the case of oral administration, the tablet may contain, in addition to the mentioned excipients, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various additives such as starch, preferably potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc may additionally be used for tableting. In the case of aqueous suspending agents, various flavouring or colouring agents may be added to the active compound in addition to the adjuvants described above.

In a second aspect, the invention provides a method of treating a subject suffering from pain associated with a nerve injury. The method comprises the step of administering to the subject an effective amount of a CCK2 receptor antagonist as described above.

Advantageously, the CCK2 receptor antagonists of the present invention have a long half-life in vivo and can be used as effective and long-lasting treatments for the treatment of pain associated with nerve damage.

Pain is an unpleasant sensory and emotional experience associated with, or described by, tissue damage (actual or potential damage). "treating" pain associated with nerve injury includes reducing or alleviating the severity, incidence or persistence of pain caused by nerve injury. Pain may be acute pain, chronic pain or operational pain. "acute pain" refers to sudden pain due to a specific cause (injury, infection, inflammation, etc.) that persists for a limited period of time, whereas "chronic pain" is often associated with medical conditions or diseases that are incurable or refractory over a long period of time. "post-operative pain" refers to pain caused by medical, dental, or other surgery/procedure, wherein the surgery/procedure may be scheduled or associated with an acute trauma.

In one embodiment herein, administration of a CCK2 receptor antagonist to a subject can reduce pain associated with nerve damage. In a preferred embodiment, the pain is chronic pain.

In embodiments where the subject is a mouse, an effective amount of a CCK2 receptor antagonist for pain relief is preferably about 0.001mg/kg, 0.01mg/kg, 0.1mg/kg, 1mg/kg, 10mg/kg, 100mg/kg, or 500 mg/kg. An effective amount of a CCK2 receptor antagonist for use in the method can be indicated by a reduction in the severity or incidence of pain symptoms in the subject over a defined period of time. It will be appreciated that the effective amount may depend on the species, weight, age and individual condition of the subject and may be determined by standard procedures.

In another embodiment, CCK receptor antagonists may be used to treat chronic pain that is refractory in nature, i.e., pain that does not function with the regimens traditionally used to treat chronic pain.

The CCK2 receptor antagonists of the present invention can be administered in combination with an effective amount of one or more analgesic compounds. The term "analgesic compound" includes drugs that are typically administered to subjects who are not resistant to current analgesic drug therapies, i.e., compounds known to treat pain.

In exemplary embodiments, the analgesic compound may be selected from the group consisting of: paracetamol (paracetamol), aspirin (aspirin), ibuprofen (ibuprofen), naproxen (naproxen), diazepam (diazepam), celecoxib (celecoxib), duloxetine (duloxetine), codeine (codeine), fentanyl (fentanyl), oxycodone (oxycodone), methadone (methadone), hydromorphone (hydromorphone), diflunisal (diflunisal), hydrocodone (hydrocodone), acetaminophen (acetaminophen), and indomethacin (indomethacin).

In an exemplary embodiment, the CCK2 receptor antagonist can be administered to a subject in the form of an epidural injection, alone or in combination with one or more analgesic compounds, to treat chronic pain.

In another aspect, the present invention relates to a pharmaceutical composition comprising as active ingredients a CCK2 receptor antagonist as described above or a pharmaceutically acceptable salt thereof, one or more antidepressant compounds as described above, and optionally pharmaceutically acceptable excipients.

In another aspect, the present invention relates to a pharmaceutical composition comprising as active ingredient a CCK2 receptor antagonist as described above or a pharmaceutically acceptable salt thereof, one or more analgesic compounds as described above, and optionally a pharmaceutically acceptable excipient.

The "pharmaceutically acceptable excipient" may include pharmaceutically acceptable carriers, diluents, preservatives, solubilizers, stabilizers, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts, buffers, coating agents, and antioxidants. Suitable excipients and techniques for formulating pharmaceutical compositions are known to those skilled in the art.

The invention therefore also relates to the use of a CCK2 receptor antagonist as described above for the treatment of a psychotic disorder, in particular depression, and to the use of a CCK2 receptor antagonist as described above for the preparation of a medicament for the treatment of a psychotic disorder, in particular depression.

The invention further relates to the use of a CCK2 receptor antagonist as described above for the treatment of pain associated with nerve injury, in particular chronic pain, and to the use of a CCK2 receptor antagonist as described above for the preparation of a medicament for the treatment of pain associated with nerve injury.

Based on the foregoing, it will be appreciated that CCK2 receptor antagonists of the invention may be useful in treating a subject suffering from both a psychiatric disorder, e.g., depression, and pain, e.g., chronic pain associated with nerve injury.

Advantageously, a single administration of a CCK2 receptor antagonist as described above may result in a high circulating concentration of CCK2 receptor antagonist for up to 8 weeks, thereby providing an effective and stable and long lasting pharmacological effect.

The experiments described below further support the antidepressant effect and analgesic properties of the CCK2 receptor antagonists according to the invention.