WO2010030681A2 - Therapeutic agents for the treatment of disorders causing the sensation of suffocation - Google Patents

Description

THERAPEUTIC AGENTS FOR THE TREATMENT OF DISORDERS CAUSING

THE SENSATION OF SUFFOCATION

Technical Field

[0001] This application relates to the field of psychiatry, and more particularly to treatment of panic and related conditions.

Background

[0002] The sensation of suffocation is an extremely unpleasant medical condition characterized by a sudden, unexpected, and often overwhelming feeling of being unable to breathe, often referred to as dyspnea or air hunger, frequently accompanied by terror and apprehension. This sensation is a hallmark of a host of mental disorders such as panic attacks and panic related disorders. Patients who suffer from panic attacks often feel a sense of impending death, a part of which is the sensation of suffocation, but the terrible sensations usually subside with time, but often reoccur. However, dyspnea can be chronic, severe, and incapacitating.

[0003] Current therapies for treating panic attacks, panic disorder, conditions related to panic disorder, and dyspnea include both pharmacological agents and psychotherapy. The principal medications prescribed for these disorders are antidepressants, anti-anxiety drugs, and beta- blockers. However, these agents usually take about 4 to 6 weeks before taking full effect, produce unwelcome physical side effects such as nausea or drowsiness, and may elicit physiological dependence. Also, these agents are often ineffective at treating the sensations of suffocation and asphyxiation that often accompany such attacks. Chronic dyspnea may require chronic opiate administration.

[0004] Thus, there is a need for more effective and immediate treatments of the sensation of asphyxiation, and more generally, of panic attacks, panic disorder, conditions related to panic disorder, and dyspnea that have reduced or no side effects.

[0005] The sensation of suffocation can be temporary or a more debilitating condition, accompanying the respiratory distress due to serious chronic disorders such as cancer, asthma, chronic obstructive pulmonary disease (COPD), congenital central hyperventilation syndrome (CCHS), and heart failure. COPD is the fourth leading cause of death in the United States. The NHBLI reports 12.1 million adults, 25 years of age and older were diagnosed with COPD in 2001 and that up to 16 million people in the U.S. may have this disorder currently, with an additional 14 million in the early stages of the disease. Asthma affects approximately 20 million Americans have asthma; 9 million US children under 18 are diagnosed with asthma. Asthma accounts for one quarter of all emergency room visits in United States each year, i.e., 2 million emergency room visits in 2001.

[0006] Often, patients who are suffering from COPD, cancer, and heart failure are terminal and the feeling of not having enough air is a constant condition that seriously affects the quality of life. It is preferable that these end-of-life situations should be moments in which the patient is alert, aware, and not feeling as if he or she is fighting for air in order to live. However, current treatments have not been able to effectively address these problems.

[0007] Current treatments for patients suffering from severe chronic respiratory distress are limited to palliative therapies such as treatment with opiates. However, palliative doses of opiates, such as morphine, produce many undesirable side affects such as decreasing the drive to breathe, which can lead to apnea. High doses of morphine also obtund the consciousness of patients who may wish to remain alert and conscious.

[0008] Thus, there is also a need for more effective treatments for the sensation of asphyxiation in terminal patients suffering from acute respiratory distress syndrome (ARDS), cancer, chronic obstructive pulmonary disease, or congestive heart failure, and who desire to minimize the use of consciousness blunting opiates such as morphine.

Summary

[0009] This application relates to the finding that pain-relieving compounds are therapeutic agents for treatment of certain mental and physical disorders, including panic and related conditions, such as the sensation of suffocation, COPD, cancer, asthma, and heart failure.

[0010] Accordingly, in one aspect, the disclosure provides a method of treating the sensation of suffocation in a patient. The method comprises identifying a patient suffering from the sensation of suffocation and administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a pain-relieving compound. In some embodiments, pain-relieving compounds include carbon monoxide (CO), compounds which release CO in vivo, and delta opioid receptor agonists, delta opioid receptor antagonists, and mixed delta opioid receptor compounds.

[0011] In some embodiments, the patient's sensation of suffocation is a result of a panic attack, panic disorder, a condition related to panic disorder, or dyspnea. Conditions related to panic disorder include agoraphobia, separation anxiety disorder, and major depression.

[0012] In further embodiments, the patient's sensation of suffocation is a result of respiratory distress caused or dyspnea. Respiratory distress may be a result of cancer, chronic obstructive pulmonary disease, or congestive heart failure.

[0013] In other embodiments, the pharmaceutical composition administered to the patient suffering from the sensation of suffocation comprises CO. In yet other embodiments, the pharmaceutical composition comprises a compound comprising a moiety which releases CO in vivo.

[0014] In certain embodiments, the compound which releases CO in vivo is a carbon monoxide-releasing molecule (CORM) selected from the group consisting of an organometallic complex comprising CO, an organometallic complex comprising CO and linked to one other therapeutic agent, a supramolecule aggregate comprised of organometallic complexes comprising CO, and organic compounds. In a further embodiment, the compound which releases CO in vivo is a supramolecule aggregate comprised of cyclodextrin and an organometallic complex comprising CO. In another embodiment, the CORM is water- soluble.

[0015] In some embodiments, the CORM is a compound of the following Formula I:

[Mo(CO)₅Y]Q

wherein Y is bromide, chloride or iodide; and Q is [NR^1-4J⁺ , where R¹, R², R³, and R⁴ are each independently alkyl.

[0016] In other embodiments, the CORM is a compound of the following Formula II:

M(CO)_xA_yB_z where M is Fe, Co or Ru; x is at least one; y is at least one; z is zero or at least one; each A is a ligand other than CO, is monodentate or polydentate with respect to M, and is selected from the amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine valine, [0(CH₂COO)₂]^2- and [NH(CH₂COO)₂]^2-; and B is optional and is a ligand other than CO. One embodiment of a CORM of Formula II is tricarbonylchloro(glycinato)ruthenium(II) (CORM-3).

[0017] In yet other embodiments, the CORM is a boranocarboxylate or carboxyborane. One specific embodiment of a boranocarboxylate CORM is sodium boranocarbonate (CORM-Al).

[0018] In other embodiments, the pharmaceutical composition administered to the patient suffering from the sensation of suffocation comprises a delta opioid receptor agonist. In one embodiment, the delta opioid receptor agonist is ADL 5859.

[0019] In other embodiments, the pharmaceutical composition administered to the patient suffering from the sensation of suffocation comprises a delta opioid receptor antagonist compound. In certain embodiments, the delta opioid receptor antagonist compound comprises naltrindole, or a 3-ether analog of naltrindole, or 17-cyclopropylmethyl-6, 7- didehydro-4-hydroxy-3-methoxy-6,7:2',3'-indolomorphinan, or naltrindole analog substituted in the indolic benzene moiety, or opioid diketopiperazines, or the indolomorphinan HS 378.

[0020] In yet other embodiments, the pharmaceutical composition administered to the patient comprises a mixed agonist compound specific for delta opioid receptors. In certain embodiments, the mixed agonist comprises N-alkyl- and N,N-dialkyl-4-[alpha-[(2S,5R)-4- allyl-2,5-dimethyl-1-piperazinyl] benzyl] -benzamides (PMID:9288176); buprenorphine; and the 1,3,5-trisubstituted 1,2,4-triazoles [PMID: 19646882].

[0021] In certain embodiments, the pharmaceutical composition administered to the patient suffering from the sensation of suffocation further comprises at least one other therapeutic agent. The at least one other therapeutic agent is useful for treating a panic attack, panic disorder, a condition related to panic disorder, or dyspnea, and can be, but is not limited to, an antidepressant agent, a selective serotonin reuptake inhibitor, a benzodiazepine, and a beta-blocker. [0022] Useful antidepressant agents include, but are not limited to, doxepin, clomipramine, nortriptyline, citalopram, trazodone, venlafaxine, amitriptyline, escitalopram, fluvoxamine, phenelzine, desipramine, tranylcypromine, paroxetine, fluoxetine, mirtazapine, nefazodone, trimipramine, imipramine, bupropion, and sertraline.

[0023] Useful selective serotonin reuptake inhibitors include, but are not limited to, paroxetine, sertraline, fluoxetine, citalopram, escitalopram, and fluvoxamine. Useful benzodiazepines include, but are not limited to, clonazepam, alprazolam, and lorazepam. Useful beta-blockers include, but are not limited to, propranolol.

[0024] In other embodiments, the pharmaceutical composition is administered to a patient suffering from the sensation of suffocation orally, sublingually, intravenously, or topically.

[0025] In yet other embodiments, the pharmaceutical composition is a gaseous composition administered to the patient by inhalation. In some embodiments, the gaseous composition comprises CO at a concentration of at least about 1 ppm to about 50 ppm. In some embodiments, the gaseous composition comprises CO at a concentration of at least about 1 ppm. In some embodiments, the gaseous composition comprises CO at a concentration of at least about 10 ppm. In some embodiments, the gaseous composition comprises CO at a concentration of no more than about 50 ppm. In some embodiments, the gaseous composition is provided to the patient for at least about 10 seconds, and in other embodiments, the gaseous composition is provided to the patient for at least about 5 minutes.

[0026] In another aspect, the disclosure provides a method for inhibiting suffocation signals emanating from the carotid body in a mammal. The method comprises contacting the mammal with a therapeutically effective amount of a pain-relieving compound.

[0027] In yet another aspect, the disclosure provides a method of treating the sensation of suffocation in a patient suffering from a panic attack, panic disorder, a condition related to panic disorder, or dyspnea. The method comprises identifying a patient suffering from the sensation of suffocation as a result of a panic attack, panic disorder, a condition related to panic disorder, or dyspnea; and administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising ADL 5859. [0028] Other features and advantages of the disclosure will be apparent from the detailed description, drawings, and from the claims.

Brief Description of the Figures

[0029] FIGS. IA - IB are graphic representations of a raw respiration recording from freely moving mice exposed to 5% CO₂; and Cθ2-induced change in rate (Fig. IA) and volume (Fig. IB) in the mice, as described in Example 1.

[0030] FIGS. 2A - 2B are graphic representations of the mean change in respiratory rate (Fig. 2A) and tidal volume (Fig. 2B) during 5% CO₂ challenge in control and mice injected with the deltas or antagonist Naltrindole in a "within-animal design," as described in Example 1.

[0031] FIGS. 3A-3B are graphic representations showing that an injection of either saline or Alprazolam (0.3 mg/kg) decrease both respiratory rate (Fig. 3A) and tidal volume (Fig. 3B) that lasted at least 30 min, as seen in the baseline measures prior to initial CO₂ exposure.

[0032] FIGS. 4A-4C are graphic representations of the tidal volume response, respiratory rate, and volume/rate of WT and delta-opioid receptor knockout mice exposed to 5% CO₂ challenge after no injection (FIG. 4A), saline injection (FIG. 4B), or Alprazolam (FIG. 4C).

[0033] FIG. 5 is a graphic representation of the tidal volume response of WT mice injected with saline, Naltrindole (0.1 mg/kg), or a combination of Naltrindole (0.1 mg/kg) and Alprazolam (0.3 mg/kg).

[0034] FIGS. 6A - 6B are graphic representations of the tidal volume response of saline-treated (FIG. 6A) and Diazepam-treated (FIG. 6B) mice.

[0035] FIGS. 7A - 7B are graphic representations of the tidal volume response of

Alprazolam-treated (FIG. 7A) and Diazepam-treated (FIG. 7B) mice. [0036] FIGS. 8A - 8B are graphic representations showing tidal volume response

(FIG. 8B) after 15 min exposure to 5% CO2 in WT (n=3) and delta-opioid receptor knockout (n=3) mice. Detailed Description

[0037] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0038] The disclosure relates to the finding that pain-relieving compounds can be used for the treatment of the sensation of suffocation. In some instances, the pain-relieving compound can be an anti-inflammatory agent. Non- limiting examples of pain-relieving compounds that are useful for treating sensations of suffocation include carbon monoxide (CO), compounds which release CO in vivo, and opioid receptor agonists, such as delta opioid receptor agonists.

[0039] CO is inhibitory to the carotid body, which is a prime peripheral monitoring station that is attuned to signals of potential asphyxiation, such as hypercapnia (high carbon dioxide concentration) and hypoxia (low oxygen concentration). The carotid body is a small cluster of chemoreceptors and cells located near the bifurcation of the carotid artery which detects changes in the composition of arterial blood flowing through it, including the partial pressure of oxygen and carbon dioxide. The carotid body is composed of two types of cell: type I (glomus) cells and type II (sustentacular) cells. The glomus cells release a variety of neurotransmitters, including acetylcholine and dopamine that trigger excitatory postsynaptic potentials (EPSPs) in synapsed neurons leading to the respiratory centers of the brain. This organ primarily functions as a sensor by responding to a stimulus, such as oxygen or carbon dioxide partial pressure. Changes in blood gases are sensed by glomus cells in the carotid body that synapse on afferent terminals of the carotid sinus nerve that projects to respiratory related neurons in the brainstem.

[0040] The carotid body emanates suffocation alarm signals in response to potential dangers of asphyxiation. These alarm signals include, but are not limited to, acute breathlessness, chronic breathlessness, panic, dyspnea, and the urge to flee. Without wishing to be bound by any particular theory, a core causal factor in the pathogenesis of panic attacks, panic disorder, and conditions related to panic disorder may be a hyperresponsive or dysregulated suffocation alarm system which includes the carotid body.

[0041] It has further been found that the carotid body's suffocation alarm system is particularly attuned to signals of potential asphyxiation, such as high concentrations of carbon dioxide in the blood. Thus, all asphyxiating circumstances should elicit panic-type reactions. However, two apparent exceptions are CO exposure and morphine overdose. Neither asphyxiation due to CO exposure nor morphine overdose causes panic, and in fact, people who are exposed to high concentrations of CO or morphine simply fade away without a panic arousal.

[0042] The effective sabotage of the suffocation alarm system by CO or morphine observed in people exposed to high levels of CO or morphine, coupled with the discovery of CO as a neurotransmitter, have been used to develop the present disclosure, which, in part, utilizes pain-relieving compounds including CO, compounds which release CO in vivo, and opioid receptor agonists as anti-panic agents. The disclosure provides, for the first time, the use of pain-relieving compounds to achieve psychotropic therapeutic benefits by inhibiting suffocation signals emanating from the carotid body. Therapeutic effects are obtained by contacting the mammal with a therapeutically effective amount of a pain-relieving compound. As used herein, the term "contacting" refers to treating, affecting, or administering to the mammal a therapeutically effective amount of a compound. As will be described in further detail, the contacting of the mammal may include, but is not limited to, oral, sublingual, intravenous, or topical routes of administration.

[0043] Another aspect of the disclosure provides for therapeutic methods of treating the sensation of suffocation in a patient, by identifying a patient suffering from the sensation of suffocation and administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a pain-relieving compound, including, but not limited to, CO, a compound which releases CO in vivo, or an opioid receptor agonist, such as a delta opioid receptor agonist. As used herein, the term "treatment" refers to the application or administration of a therapeutic agent to a patient who has a disease, disorder, symptom, or predisposition toward a disease or disorder. The sensations of suffocation may include acute breathlessness, chronic shortness of breath, panic, the urge to flee, and other alarm signals emitted by the suffocation alarm system. [0044] In one embodiment, the sensation of suffocation suffered by the patient is a result of a panic attack, panic disorder, a condition related to panic disorder, or dyspnea. One of skill in the art can readily identify a patient suffering from the sensation of suffocation resulting from one of these disorders, using knowledge in the art and references such as Harrison 's Principles of Internal Medicine (McGraw-Hill, Inc., New York), and then administer a pharmaceutical composition of the disclosure to the patient accordingly to treat the sensation of suffocation.

[0045] As used herein, a "panic attack or disorder" refers to the sudden, unexpected, and often overwhelming feeling of terror and apprehension, or acute physical distress, accompanied by somatic symptoms in multiple organ systems such as dyspnea, palpitations, and faintness. A typical panic attack may begin abruptly and without warning while a patient is involved in a relatively nonthreatening and nonstressful activity. Initial symptoms often include feeling flushed, lightheaded, dizzy, faint, sweaty, and overwhelmed by feelings of terror and apprehension. Dyspnea may occur with a subjective sense of choking or smothering, and palpitations or chest pain are often so severe that patients believe they are having a heart attack.

[0046] Disorders related to panic include agoraphobia, separation anxiety disorder, and major depression. As used herein, "agoraphobia" refers to the fear of being alone or in public places for fear that if panic or similar sensations occur, they will not be able to get to help or that help will be prevented from arriving. "Separation anxiety disorder" refers to a condition in which the individual has excessive anxiety regarding separation from home or from people to whom the individual has a strong emotional attachment.

[0047] As used herein, "major depression" refers to any "mood disorder" or "anxiety disorder" described in the Diagnostic and Statistical Manual (referred to herein as the "DSM- IV-TR", American Psychiatric Association, 2000). Mood disorders include, but are not limited to, "depressive disorders" (referenced as 296.2x, 296.3x, 300.4, 311 in the DSM-IV- TR), "bipolar disorders" (referenced as 296.Ox, 296.40, 296.4x, 296.5x, 296.6x, 296.7,296.89, 301.13, 296.80 in the DSM-IV-TR) and "mood disorder not otherwise specified" (referenced as 296.90 in the DSM-IV-TR). "Anxiety disorders" include, but are not limited to, "panic disorders" (referenced as 300.01, 300.21 in the DSM-IV-TR), "phobic disorders" (referenced as 300.29, 300.22, 300.23 in the DSM-IV-TR), "obsessive-compulsive disorder" (referenced as 300.3 in the DSM-IV-TR), "post-traumatic stress disorder" (referenced as 309.81 in the DSM-IV-TR), "acute stress disorder" (referenced as 308.3 in the DSM-IV-TR), "generalized anxiety disorder" (referenced as 300.02 in the DSM-IV-TR) and "anxiety disorder not otherwise specified" (referenced as 300.00 in the DSM-IV-TR). Extensive lists of symptoms and diagnostic criteria for each of these disorders are found in the DSM-IV-TR sections cited above.

[0048] As used herein, "dyspnea" refers to an acute hunger for air or a sense of shortness of breath. The degree of dyspnea is subjective in nature; patients with dyspnea may describe the sensation as "cannot get enough air," "air does not go all the way down," "smothering feeling in the chest," "tightness in the chest," and a "choking sensation." Episodes of dyspnea may be a result of physical exertion, but may also come about at rest. Dyspnea is often diagnosed in a patient suffering from an obstructive disease of the airways (e.g. asthma, emphysema, alveolar insufficiency), diffuse parenchyma lung diseases (e.g. acute pneumonia, acidosis, and pneumoconiosis), pulmonary vascular occlusive diseases (e.g. pulmonary emboli), diseases of the chest wall or respiratory muscles (e.g. severe kyphoscoliosis, pectus excavatum, and spondylitis), heart disease, or anxiety.

[0049] In another embodiment, the sensation of suffocation suffered by the patient may be experienced as dyspnea or respiratory distress. As used herein, "respiratory distress" refers, in part, to physically labored ventilation or respiratory efforts. Respiratory distress may be a result of many other disorders, including, but not limited to, adult respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, congenital central hyperventilation syndrome, cancer, or heart failure.

[0050] As used herein, "adult respiratory distress syndrome" (ARDS) refers to a severe lung disease characterized by a diffuse inflammation of lung parenchyma and severe loss of oxygen in arterial blood (hypoxemia). Conditions which may lead to ARDS include pulmonary infections, aspiration, inhalation of toxins, narcotic overdose, immunologic response to host antigens, nonnarcotic drug effects, effects of nonthoracic trauma with hypotension, and postcardiopulmonary bypass.

[0051] As used herein, "chronic obstructive pulmonary disease" (COPD) refers to chronic lung disorders that result in blocked air flow, or alveolar insufficiency in gas exchange, in the lungs. A non-limiting example of a COPD that causes respiratory distress leading to sensations of suffocation is emphysema.

[0052] As used herein, "congenital central hyperventilation syndrome" (CCHS) encompasses a genetic disorder of the central nervous system in which individuals are completely insensitive to hypercapnia, or carbon dioxide retention. This renders the individual apneic during sleep, when CO₂ is the sole source of the respiratory drive. CCHS adults do not experience either suffocation sensations or respiratory stimulation in asphyxial conditions. Some of the genetic factors that cause CCHS have been identified, one of which is also linked to sudden infant death syndrome (SIDS).

[0053] As used herein, "sudden infant death syndrome" (SIDS) is a syndrome marked by the symptoms of sudden and unexplained death of an apparently healthy infant aged one month to one year. Without wishing to be bound by any particular theory, hyposensitivity of the asphyxial alarm system may be involved in the pathophysiology of SIDS. For example, parental smoking may produce significant infant exposure to CO and pulmonary irritants to inhibit the asphyxial alarm system.

[0054] Dyspnea and respiratory distress in cancer patients may be caused by the malignancy itself, therapies, comorbid medical conditions, and general muscle weakness or wasting. The malignancy may be cancer such as brain cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colorectal cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, leukemia, myeloma, multiple myeloma, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, Hodgkin's disease, lymphocytic lymphomas, non- Hodgkin lymphoma, cancer of the bladder, liver cancer, renal cancer, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas), glioma or fibrosarcoma. [0055] Dyspnea and respiratory distress may also be a result of heart failure. As used herein, "heart failure" refers to an inability of the heart to maintain an adequate output of blood from one or both ventricles of the heart to meet the metabolic demands of the tissues. With a markedly weakened left ventricle or right ventricle or both, the volume of blood presented to the heart is in excess of the heart's capacity to move it along. Consequently, fluid builds up behind the heart. With a weakened left ventricle or right ventricle or both, there is a shift of large volumes of blood from the systemic circulation into the pulmonary (lung) circulation. If the inability to move the volume of blood forward is due to a left heart problem without the right side failing as well, blood continues to be pumped into the lungs by the normal right heart, while it is not pumped adequately out of the lungs by the left heart. As the volume of blood in the lungs increases, the pulmonary vessels enlarge, pulmonary venous congestion develops, and, once the pulmonary capillary pressure rises above a critical point, fluid begins to filter out of the capillaries into the interstitial spaces and alveoli (air sacs in the lungs where exchange of oxygen and carbon dioxide occurs), resulting in pulmonary edema. Subsequently this can lead to pleural effusion (effusion is the escape of fluid into a part) and abdominal effusion. If the abnormality lies in the right heart or the pulmonary arteries, limiting the ability to move blood forward, then congestion occurs behind the right heart (causing pleural effusion and/or build up of fluid in the abdomen).

[0056] In some embodiments, the methods of the disclosure described herein comprise the administration of a pharmaceutical composition that may comprise CO or a compound which releases CO in vivo or which comprises a moiety which releases CO in vivo. A moiety which releases CO in vivo includes moieties which comprise CO and moieties which generate CO.

[0057] In yet other embodiments, the pharmaceutical composition comprises a carbon monoxide-releasing molecule. As used herein, a "carbon monoxide-releasing molecule" (CORM) refers to a molecule that slowly releases small amounts of CO in the target tissue. Carbon monoxide may be generated from precursor compounds either by spontaneous release or by a metabolic process. As used herein, "spontaneous release" refers to thermally, chemically, oxidatively, or light induced release. The release of CO from the precursor compound may be assisted by donor molecules which are ubiquitous in the organism, such as water, proteins, or nucleotides. As used herein, "release by metabolic process" refers to release with the involvement of one or more enzymes, such as, for example, cytochrome P450 and glutathione S-transferase.

[0058] The pharmaceutical composition administered to a patient suffering from the sensation of suffocation may comprise CORMS such as one selected from the group consisting of an organometallic complex comprising CO, an organometallic complex comprising CO and linked to one other therapeutic agent, a supramolecule aggregate comprised of organometallic complexes comprising CO, and organic compounds. The CORM may alternatively be a supramolecule aggregate comprising cyclodextrin and an organometallic complex comprising CO. The CORM may also be water-soluble.

[0059] CORMS are well-described in the patent literature. For example, U.S. Patent

Nos. 7,011,854 and 7,045,140, and U.S. Patent Pubs. 2007/0065485, 2006/0147548, 2007/0207217, 2006/0233890, and 2006/0148900 describe CORMS that can be used in the presently described methods.

[0060] Examples of CORMS that can be used include the following classes: Class 1 :

CO-containing organometallic complexes dissolved in physiologically compatible support; Class 2: CO-containing organometallic complex linked to at least another pharmacologically important molecule, such as a carrier or a drug (e.g., an anti-panic agent), for example, by means of an appropriate spacer; Class 3 : supramolecule aggregates made of CO-containing organometallic complexes encapsulated in cyclodextrin hosts and/or other appropriate inorganic or organic supports; Class 4: CO-containing inorganic complexes bearing several categories of polidentate ligands containing N and/or S donors that function as reversible CO carriers; Class 5: CO-containing inorganic complex bearing ligands, e.g. polidentate ligands, containing N and/or S donors that function as reversible CO carriers, linked to at least another pharmacologically important molecule, such as a carrier or a drug (e.g., an anti-panic agent), for example, by means of an appropriate spacer; Class 6: organic substances that release CO either by an enzymatic process or by decarbonylation, dissolved in physiologically compatible supports; and Class 7: organic substances that release CO either by an enzymatic process or by decarbonylation, e.g., dichloromethane, encapsulated either in cyclodextrin hosts and/or other appropriate inorganic or organic supports.

[0061] Class 1 comprises either simple 18 electron organometallic carbonyl complexes or modifications thereof designed to improve either their solubility in physiological media or their compatibility with membranes and biomolecules or tissues. The metals that may be used include first transition row biologically active metals (V, Cr, Mn, Fe, Co, Ni, Cu) as well as second (Mo, Ru, Rh, Pd) and third row elements (W, Re, Pt, Au), that appropriately bind the CO ligand. A large number of these compounds bears the cyclopentadienyl ligand (Cp) or derivatives thereof (indenyl, CpR5, and the like) hereby abbreviated as CpR(X), which enable the above-mentioned modifications, and impart some steric protection to the metal center with the corresponding higher reactivity control. The oxidation state of the metal in most of the complexes resembles the one usually found under biological conditions thereby facilitating later metabolization, after CO release.

[0062] In the exemplary compounds listed immediately below, the term "pseudo- halide" is a general name given to mono-anionic ligands isoelectronic with the halides, e.g., thiocyanates, cyanates, cyanides, azides, etc. The term "hydrocarbyl chain" is the general name of a hydrocarbon radical comprising aliphatic CH₂ and/or aromatic residues, e.g., (CH₂)_n, n=2, 3, etc. or (CH₂)_n, (C₆H₄)_m, C₆H₅CH₂, etc. Alkyl is the general name given to the radical of an aliphatic hydrocarbon chain, e.g. methyl, ethyl, etc. Aryl is the general name given to a radical of an aromatic ring, e.g., phenyl, to IyI, xylyl, etc.

[0063] Several modifications can be envisaged to improve higher biological compatibility and solubility. One possibility is to attach carboxylic, peptide or sugar derivatives to the cyclopentadienyl moiety. An exemplary compound is depicted for one Mn complex; similar derivatives can be made with compounds containing other metals, as well as for indenyl and other CPR(X) derivatives.

[0064] Class 2 takes advantage of the synergistic effects arising from the combination of two biologically active molecules, which both have beneficial effects. Examples for such drug-drug conjugates have been described in U.S. Pat. No. 6,051,576.

[0065] The above mentioned spacers comprise a variety of functions under the following specifications: the value of "n" in the linear hydrocarbon chain is an integer more specifically 1, 2, 3, 4: X is a general symbol for a substituent at the aromatic ring, namely, alkyl, aryl, alkoxy, aryloxl, halogen atom, thiolate; "peptide chain" represents a short chain of natural amino acids ranging from 1 to 4; by "sugars" it is meant the use of a mono-, di- or polysaccharide either protected or modified with adequate protection to increase lipophilicity and/or assure chemical stability of the drug-drug conjugate molecule, for example, with protective groups, such as esters, acetals, and silyl derivatives.

[0066] The definition of X given immediately above can be extended to carboxylates and amino acids in the cases where X is directly bound to the metal as in some of the exemplary compounds depicted in the next scheme.

[0067] A second group of compounds bears the bioactive molecule, e.g. aspirin, diphosphonate, bound directly to the metal, which can be achieved in several different manners as schematized below for the case of some iron and molybdenum cyclopentadienyl carbonyls, among others. The term "hydrocarbyl chain" is the general name of a hydrocarbon radical comprising aliphatic CH₂ and/or aromatic residues, e.g., (CH₂)_n, n=2, 3, etc. or (CH₂)_n, (C₆H₄)_m, C₆H₅CH₂, etc.

[0068] Class 3 comprises encapsulated supramolecular aggregates made of CO- containing organometallic complexes. Controlled delivery of drugs into the organism is an important issue, especially in the case of drugs, which have undesired toxic effects if present systemically or at high local concentrations. CO release is a potential problem inasmuch as it can be toxic at high concentrations. For certain applications, a slow release of CO in the blood or in specific target tissues is desirable. Encapsulation within host molecules that are non-toxic is one way to achieve a sustained release of active drugs in the organism. This strategy minimizes the undesired effects that may result from abrupt increases in the concentration and/or availability of a potentially toxic drug.

[0069] Cyclodextrins are well known hosts for many drugs and organic molecules and, recently have been applied to host organometallic molecules and enhance their delivery through physiological barriers or membranes. In this respect cyclodextrin has been found to be beneficial for increasing delivery of lipophilic drugs at the skin barrier (Loftsson, et al. (2001) Int. J. Pharm., 225:15). Cyclodextrin mediated supramolecular arrangements protect organometallic molecules for prolonged time periods and mask their reactivity, thereby increasing their selectivity towards specific reagents. The hydrophobic part of carbonyl complexes as those exemplified under Class 1 above, fit inside β- or γ-cyclodextrin, or similar structures, with the CO groups facing the reaction medium and the organic ligands buried in the cavity. The resulting reduction in reactivity allows for the extension of the range of therapeutic CO-releasing complexes to cationic and anionic ones. Such charged complexes are more reactive and lose CO faster than the neutral ones when unprotected.

[0070] Liposomes and other polymeric nanoparticle aggregates are also useful carriers to target the delivery of CO-releasing organometallic complexes and the combined use of cyclodextrins with such aggregates is also useful for drug release (Duchene, et al. (1999), Adv. Drug Delivery Rev., 36:29).

[0071] Nonlimiting exemplary compounds include organometallic molecules such as

(C₆H_{6 X}R_X)M(CO)₃ (M=Cr, Mo, W); (CpR₅)M(CO)₃X (M=Cr, Mo, W); (CpR₅)M(CO)₂X (M=Fe, Ru); (CpR₅)M(CO)₂ (M=Co, Rh) where R represents H, alkyl or other small functional group like methoxide, halide, carboxylic esters.

[0072] CO can be generated in vivo in a mammal by administering to the mammal a compound comprising a supramolecule aggregate comprised of cyclodextrin and a CO- containing organometallic complex of, e.g., the formula (C₆H₆-XR_x)M(CO)₃, where (M=Cr, Mo, W); (CpR₅)M(CO)₃X, where (M=Cr, Mo, W); (CpR₅)M(CO)₂X, where (M=Fe, Ru); or (CpR₅)M(CO)₂, where (M=Co. Rh); where Cp is cyclopentadienyl, R represents H, alkyl, methoxide, halide or a carboxylic ester, subscript x is an integer from 1 to 6, X is alkyl, aryl, halide. OR', SR', O₂CR', S₂CNR'₂, or S₂P(OR')₂, and R' is alky or aryl.

[0073] Mesoporous materials that can be used with the aggregate compounds described above are chemically inert three-dimensional molecules with infinite arrays of atoms creating channels and cavities of well defined pore size. These molecules are well suited to host organic and organometallic molecules in their pores. In the presence of biological fluids, smaller molecules undergoing acid-base and/or polar interactions with the inner walls of the pores slowly displace the included drugs, resulting in a controlled delivery of the active principle. Such aggregates have been prepared from M41S materials using organometallic molecules like those depicted under system 1 above. Examples include, but are not limited to, MCM-41 (linear tubes) and MCM-48 (cavities and pores). [0074] Class 4 comprises CO-containing inorganic complexes bearing ligands containing N and/or S donors that function as reversible CO carriers. Classical inorganic complexes bearing macrocyclic ligands on an equatorial plane of an octahedral coordination sphere are known to reversibly bind CO much in the same way as hemoglobin. The capacity to bind CO can be "tuned" by the nature of both the macrocycle and the ancilliary ligand trans to CO. A similar behavior has also been reported for other Fe(II) complexes bearing ligands that are much simpler than the porphyrin macrocycles that are the CO acceptor sites in hemoglobin and other heme containing proteins. In order to develop suitable CO delivering drugs, the later type of non-hemic complexes was chosen to avoid interference with the biological heme carriers, heme metabolism, and potential toxicity of heme or heme-like molecule. The complexes selected bear bidentate N donors (diamines, diglyoximes) or bidentate N₅S donors of biological significance, like aminothiols or cysteine. Ancilliary ligands are N donors also of biological significance like imidazole, hystidine, and others. The complexes are soluble in aqueous media.

[0075] In the exemplary compounds immediately below, the term pyridines refers to derivatives of the C5H5N ring (pyridine) bearing alkyl (R), alkoxy (OR), carboxy (C(O)OR), nitro (NO₂), halogen (X), substituents directly bound to the one or more positions of the C5 carbon ring, e.g. CH3C5H4N, O2NC5H4N. Amino-thiols refers to compounds bearing both the NH₂ (amino) and SH (thiol) functions bound to a hydrocarbon skeleton, e.g. H₂NCH₂CH₂SH, 1,2-C₆H₄(NH₂)(OH). A similar definition applies to amino alcohols, whereby the SH function is replaced by the OH (alcohol) function. The term amino acids refers to naturally occurring single amino acids coordinated in a bidentate fashion by the NH₂ and the COO functions as schematically depicted. Glyoximes are bidentate N donors, bearing either alkyl or aryl substituents on the hydrocarbon chain binding the two N atoms, as depicted in the first example below for a diaryl glyoxime. Diimines present a similar structure whereby the OH groups in the diglyoximes are replaced by alkyl or aryl groups. An extension of this family of ligands includes also 2,2'-bypiridines, e.g., 2,2'-dipyridyl, and phenanthrolines.

[0076] Following the strategy outlined above for Class 2 compounds, CO carriers of the type described as Class 4, but modified by linking the ligands to other biologically active molecules via an appropriate spacer, may be prepared as Class 5 compounds.

[0077] Class 6 comprises organic substances that release CO either by an enzymatic process or by decarbonylation. In spite of the fact that decarbonylation is not a very common type of reaction in organic chemistry, some organic substances are known to liberate CO upon treatment with either bases, acids, or radical initiators depending on their nature. These substances fall into the following groups: polyhalomethanes of the general form CH_nXyX'4-(_n+y) (X and or X'=F, Cl, Br, I) trichloroacetic acid, and its salts, organic and inorganic esters and sulfmates thereof, triaryl carboxylic acid, formic acid, oxalic acid, α- hydroxyacids and α-ketoacids, esters and salts thereof, under acid conditions; trialkyl and trialkoxybenzaldehydes under acid catalysis; aliphatic aldehydes with radical initiators, e.g., peroxides or light. For the polyhalomethanes, the values of n and y vary in the following way: for n=0, y=l, 2, 3, 4; for n=l, y=l, 2, 3; for n=2, y=l, 2; for n=3, y=l. In the above exemplary compounds, the term "salt" applies to the ionic derivative of the conjugate base of a given protonic acid, namely a carboxylate, with a main group element ion, namely Na⁺, K⁺. Alkyl is the general name given to the radical of an aliphatic hydrocarbon chain, e.g. methyl, ethyl, propyl, butyl, etc. The alkyl group can be branched or straight chain. Aryl is the general name given to a radical of an aromatic ring, e.g., phenyl, tolyl, xylyl, etc. The aryl group will typically have about 6 to about 10 carbon atoms. Ester is the general name given to the functional group — C(O)OR (where R=alkyl, aryl).

[0078] The first two categories produce dichlorocarbene, which, under physiological conditions, are metabolized to CO. In the case of dichloromethane, cytochrome P-450 has been shown to be responsible for the liberation of CO in vivo.

[0079] The third group of compounds releases CO under acid catalysis and is sensitive to the aryl substitution pattern. The fourth group, which includes trialkyl and triaryl substituted aldehydes, may also act in the same way. Strong activating groups on the aryl ring favor CO liberation under acid conditions. The radical initiated decomposition of aliphatic aldehydes, induced by peroxides or light, produces CO under very mild conditions. The value of "n", the number of substituents (alkyl, aryl, alkoxy, aryloxy) on the aromatic ring, can vary from 0 to 5, and in some embodiments may be 1, 2, or 3

[0080] Class 7 comprises encapsulated organic substances that release CO either by an enzymatic process or by decarbonylation. This system comprises the same molecules described under Class 6, but includes their encapsulation in host-guest supermolecules, liposomes, cyclodextrins, and other polymeric materials that are able to produce nanoencapsulated drug delivery vectors.

[0081] Exemplary CORMS, for example from Classes 1-7 described above, that can be used with the methods of the disclosure include those of the following Formula I:

[Mo(CO)₅Y]Q

wherein Y is bromide, chloride or iodide; and Q is [NR^{1 4}]⁺ , where R¹, R², R³, and R⁴ are each independently alkyl.

[0082] The compounds of Formula I provide convenient stability under air at room temperature to allow easy manipulation. Moreover, the compounds of Formula I provide the advantage of improved stability and solubility in water, including under the acidic pH range found, for example, in the gastric fluid. Without wishing to be bound by theory, this stability may derive from the lower basicity of the halide anion.

[0083] The compounds of Formula I bearing a tetraalkylammonium cation also provide improved stability in water at physiologic pH relative to their analogs with alkaline cations, even when such an alkaline cation is stabilized by a cyclic or acyclic chelating polyether. Again without wishing to be bound by theory, this stability in water may derive at least in part from the favorable cation-anion interaction provided by a tetraalkylammonium cation.

[0084] In addition, the compounds of Formula I provide enhanced release of carbon monooxide, for example, in response to attack by radical oxygen species, relative to thermally induced carbon monoxide release (substitution) in the absence of such species. Since the onset of the release is very facile, the compounds of Formula I also provide efficient release of carbon monoxide at an inflammatory site in an animal where radical oxygen species can be generated or accumulated in biologically elevated concentrations. In some embodiments, Y is bromide, chloride, or iodide. [0085] Q may be a tetraethylammonium cation, a tetra(n-butyl)ammonium cation, a tetra(n-propyl)ammonium cation, a tetra(i-propyl)ammonium cation or a tetramethylammonium cation.

[0086] In some embodiments, R¹, R², R³, and R⁴ are (C₁-C₁₂)-alkyl, (C₁-C₈)-alkyl,

(C₁-C₆)-alkyl, or (C₁-C₄)-alkyl.

[0087] The compound of Formula I may be one of the following compounds:

[0088] Other exemplary CORMS that can also be used with the methods of the disclosure include those of the following Formula II:

M(CO)xAyBz

where M is Fe, Co or Ru; x is at least one; y is at least one; z is zero or at least one; each A is a ligand other than CO, is monodentate or polydentate with respect to M, and is selected from the amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine valine, [0(CH₂COO)₂]^2- and [NH(CH₂COO)₂]^2-; and B is optional and is a ligand other than CO.

[0089] The term "amino acid" as used herein includes the species obtained by loss of the acidic hydrogen, such as glycinato.

[0090] B_z represents one or more optional other ligands. There are no particular limitations on B, and ligands such as halides, e.g., chloride, bromide, iodide, and carboxylates, e.g., acetate may be used.

[0091] M is selected from Fe, Ru and Co. In some embodiments, these metals are in low oxidation states.

[0092] In some embodiments, the compound of Formula II is tricarbonylchloro(glycinato)ruthenium(II) (CORM-3).

[0093] Other CORMS that can be used with the methods of the disclosure include boranocarboxylates or carboxyboranes, which are carboxylate adducts of borane and derivatives of borane. Boranocarbonates generally contain a group of the form -COO- or COOR (where R is H or another group) attached to the boron atom. An exemplary boranocarbonate CORM is sodium boranocarbonate (CORM-Al).

[0094] Exemplary boranocarbonates have the molecular structure including the moiety:

[0095] In some embodiments, three hydrogen atoms are attached to the boron

(BH3-CO-). In other embodiments, a carboxylate group is attached to boron, e.g., -COO-, - COOH-, -COOX where X may be any suitable esterifying group acceptable pharmaceutically.

[0096] The boranocarbonate compound may have an anion of the formula:

BH_x(COQJ_yZ₂ wherein x is 1 , 2 or 3; y is 1 , 2 or 3; z is 0, 1 or 2; x + y + a = 4; each Q is O-, representing a carboxylate anionic form, or is OH, OR, NH₂, NHR, NR₂, SR or halogen, where R is alkyl; each Z is halogen, NH₂, NHR, NR'₂, SR or OR where each R' is alkyl. Since this formula is analogous to the borano anion BH4-, the structure generally is an anion. It may be a divalent anion when one (COQ) is present as (COO-). If the structure is an anion, a cation is required. Any physiologically suitable cation may be employed, such as a metal cation, including an alkali metal ion (e.g. , K⁺ or Na⁺) or an alkaline earth metal cation (e.g. , Ca⁺⁺ or Mg⁺⁺). Alternatively, non-metal cations might be employed, such as NR₄ ⁺ where each R is H or alkyl or PR₄ ⁺ where R is alkyl. The cation may be selected in order to achieve a desired solubility of the compound.

[0097] In some embodiments, the boranocarbonate is soluble and is present in solution in a suitable solvent, e.g., an aqueous solvent. Other possible solvents are ethanol, DMSO, DMF and other physiologically compatible solvents.

[0098] In some embodiments, the methods of the disclosure described herein comprise the administration of a pharmaceutical composition that comprises an opioid receptor agonist. There are at least three different opioid receptors (mu, delta, and kappa) that are present in both central and peripheral nervous systems of many species, including humans (Lord, J. A. H., et al, (1977) Nature 267: 495). Activation of the delta opioid receptors has been found to induce analgesia in various animal models (Moulin, et al., (1985) Pain 23: 213). The delta opioid receptor has also been identified as having a role in circulatory systems. Ligands for the delta receptor have also been shown to possess immunomodulatory activities (Dondio, et al., (1997) Exp. Opin. Ther. Patents, 10: 1075) and to promote organ and cell survival (Su, T-P, (2000) Journal of Biomedical Science 9(3): 195- 199). While it is known that ligands for the delta opioid receptor are useful as analgesics, the present disclosure provides, for the first time, the use of delta opioid receptor agonists, antagonists, and mixed agonists for the treatment of disorders causing the sensation of suffocation.

[0099] As used herein, the term "ligand" refers to a compound that binds to a receptor to form a complex, and includes, agonists and partial agonists.

[0100] As used herein, the term "agonist" refers to a compound that may bind to a receptor to form a complex that may elicit a full pharmacological response, which is typically peculiar to the nature of the receptor involved and which may alter the equilibrium between inactive and active receptor.

[0101] The pharmaceutical composition administered to a patient suffering from the sensation of suffocation may comprise delta opioid receptor agonist compounds such as one selected from formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, as described in U.S. Patent Publication 2008/0102031, incorporated by reference herein in its entirety.

[0102] In some embodiments, the disclosure provides delta opioid receptor agonist compounds of formula I:

wherein:

R¹ and R³ are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R¹ and R³ when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; R² is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R¹ and R² when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R² and R³ when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; provided that R² is not

each R^ais independently H or alkyl; each R^bis independently H, alkyl, or aryl; n is the integer 0, 1, 2 or 3; A and B are each independently H, fluoro, or alkyl, or together form a double bond between the carbon atoms to which they are attached; R⁴ is — Y — W; Y is a single bond, C(R^a)(R^b), C(R^a)(R^b)C(R^a)(R^b), or C(R^a)(R^b)C(R^a)(R^b)C(R^a)(R^b); W is aryl or heteroaryl; X is -CH₂-, —O-, -S-, —SO, -SO₂, or -N(R⁵)-; R⁵ is H, alkyl, cycloalkyl, — (CH₂)-alkenyl, — (CH₂)-alkynyl, aryl, — COR^b, or — SO₂R^b; and J forms a 6- membered aryl or a 5- or 6-membered heteroaryl ring when taken together with the carbon atoms to which it is attached; provided that when: (a) J taken together with the carbon atoms to which it is attached forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, S — C_1-4 alkyl, C_1-4 alkyl, and C_1-4 alkoxy, the latter two optionally substituted with one or more halogens or with C_1-4 alkoxy; W is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C_1-6 alkyl, C_1-6 alkoxy, phenyl, phenoxy, 1,3-benzodioxazolyl, or 2,2-difluoro-1,3- benzodioxazolyl, — NH₂, — N(C_1-4 alkyl)₂, and pyrrolyl; n is 1, R¹ and R³ are each H, A and B together form a double bond between the carbon atoms to which they are attached, Y is a single bond; and X is — O — ; then R² is other than H or methyl; and provided that when: (b) J taken together with the carbon atoms to which it is attached forms a phenyl ring, W is phenyl substituted with 0-3 groups selected from the group consisting of: fluoro, hydroxy, C_1- 6 alkoxy optionally substituted with one or more fluoro, C₂_6 alkenyloxy, and — S — C_1-4 alkyl, n is 1 , R¹ and R³ are each H, A and B together form a double bond between the carbon atoms to which they are attached, Y is a single bond; and X is — O — ; then R² is other than H or benzyl; and provided that when: (c) J forms a 6-membered aryl ring, it is not substituted with:

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

[0103] In some embodiments of formula I compounds, J is — C-D-E- or — C-D-E-

F — wherein C, D, E and F are each independently — O — , — S — , — SO — , — SO₂ — , =N — , =CH — or — NH — ; wherein the latter two moieties are each independently optionally substituted; provided that each — O — ring atom within J is directly attached only to carbon or nitrogen atoms; provided that each — S — ring atom within J is directly attached only to carbon or nitrogen atoms; and provided that when J is — C-D-E-F — , at least one of C, D, E and F is =CH— .

[0104] In some embodiments of formula I compounds, X is — CH₂ — , — O — , — S — ,

—SO, or — SO₂,- CH₂- or —O-, or —0—.

[0105] In other embodiments of formula I compounds, J, taken together with the carbon atoms to which it is attached, forms an optionally substituted 6-membered aryl ring, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl ring. J is optionally substituted, including fully substituted, phenyl, 3-pyridinyl, 4-pyridinyl, 5- pyridinyl, 6-pyridinyl, thienyl, oxazolyl, 1,2,5-oxadiazolyl, imidazolyl, N-methylimidazolyl or indolyl.

[0106] In certain embodiments of formula I compounds, at least one of R¹ and R³ is

H. In other embodiments of formula I, R¹ and R³ are each independently H, alkyl, alkenyl, or alkynyl; R¹ and R³ are each independently H, C₁-C₃ alkyl, C₂-C₃ alkenyl, or C₂-C₃ alkynyl; or R¹ and R³ are each independently H, C₁-C₃ alkyl, or C₂-C₃ alkenyl.

[0107] In certain embodiments of formula I compounds, R² is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl; H or alkyl; alkyl or lower alkyl. [0108] In certain embodiments of formula I compounds, n is the integer 1.

[0109] In certain embodiments of formula I compounds, A and B are taken together from a double bond between the carbon atoms to which they are attached; A and B are taken together to form a double bond between the carbon atoms to which they are attached and n is the integer 1 ; A and B are taken together to form a double bond between the carbon atoms to which they are attached, n is the integer 1 and at least one of R¹ and R³ is H.

[0110] In certain embodiments of formula I compounds, A and B are each H; A and B are each H and n is the integer 1; A and B are each H, n is the integer 1 and at least one of R¹ and R is H.

[0111] In certain embodiments of formula I compounds, R is aryl substituted with

Q=O)NR¹¹R¹², wherein:

R¹¹ is H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or COR¹²; R¹² is H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, or R¹¹ and R¹² are taken together with the nitrogen atom to which they are attached to form a 4- to 8- membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may be optionally replaced by — O — , — S — , — SO — , — SO₂ — , — NH — , — N(alkyl)-, or — N(aryl)- groups.

[0112] In other embodiments, the disclosure provides delta opioid receptor agonist compounds of formula II:

wherein:

R⁶, R⁷, R⁸ and R⁹ are each independently H or — (CH₂)_mR¹⁰; m is the integer 0, 1, 2, 3, or 4; each R¹⁰ is independently alkyl, halo, perhaloalkyl, —OR⁵, -OCF₂H, -OCF₃, -CN, — CO₂R⁵, - Q=O)NR¹¹R¹², -SC=O)₂R¹³ -SC=O)₂NR¹¹R¹², -NR¹¹R¹², -NR¹⁴C(=O)R¹⁵,

— NR¹⁴SC=O)₂R¹⁵, aryl, or heteroaryl; each R¹¹ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or COR¹²; each R¹² is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, or R¹¹ and R¹² taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may be optionally replaced by — O — , — S — , — SO — , — SO₂ — , — NH — , — N(alkyl)-, or — N(aryl)- groups; each R¹³ is independently — OH, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; each R¹⁴ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheterocycloalkyl, aralkyl, or heteroarylalkyl; and each R¹⁵ is independently alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl.

[0113] In certain embodiments of formula II compounds, R¹ and R³ are each H. In certain embodiments of formula II, R⁴ is aryl substituted with — CC=O)NR¹¹R¹².

[0114] In yet other embodiments of formula I compounds, the disclosure provides compounds of formula III:

wherein:

R⁶, R⁷, R⁸ and R⁹ are each independently H or — (CH₂)_mR¹⁰; m is the integer 0, 1, 2, 3 or 4; each R¹⁰ is independently alkyl, halo, perhaloalkyl, —OR⁵, -OCF₂H, -OCF₃, -CN, — CO₂R⁵, —C(=0)NR^πR¹², —S(=O)₂R¹³, -SC=O)₂NR¹¹R¹², -NR¹¹R¹², — NR¹⁴C(=O)R¹⁵, — NR¹⁴S(=O)₂R¹⁵, aryl, or heteroaryl; each R¹¹ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or COR¹²; each R¹² is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroarylalkyl, or R¹¹ and R¹² taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring, wherein 1 or 2 of the heterocycloalkyl ring carbon atoms independently may be optionally replaced by — O — , — S — , — SO — , — SO₂ — , — NH — , — N(alkyl)-, or — N(aryl)- groups; each R¹³ is independently — OH, alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or alkylcycloalkyl; each R¹⁴ is independently H, alkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheterocycloalkyl, aralkyl, or heteroarylalkyl; and each R¹⁵ is independently alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl.

[0115] In certain embodiments of formula II compounds, R¹ and R³ are each H.

[0116] In certain embodiments of formula II compounds, R⁴ is aryl substituted with

_C(=0)NR^πR¹².

[0117] In certain embodiments of the disclosure, the compound is selected from the group consisting of:

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-6-fluoro-spiro[2H,l-benzopyran-2,4'- piperidine]hydrochloride;

4-[(4-N,N-diethylaminocarbonyl)phenyl]-6-hydroxyspiro[2H,l-benzopyran-2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-3,4-dihydrospiro[2H,l-benzopyran-2,4'- piperidine]hydrochloride;

4- [(4-N,N-diethylaminocarbonyl)phenyl] -N-methyl-spiro [2H, 1 -benzopyran-2,4 '-piperidine] ;

4-[(4-N-ethylaminocarbonyl)phenyl]spiro[2H,l-benzopyran-2,4'-piperidine];

4-[(4-N-propyl-N-cyclopropylmethylaminocarbonyl)phenyl]-spiro[2H,l-benzopyran-2,4'- piperidine];

4-[4-(isoindolineaminocarbonyl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine]; 4-[4-(4-carboxypiperidineaminocarbonyl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[4-(2H-tetrazolyl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[4-(4-carboxypropyl-tetrazol-2-yl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-(3-pyridyl)-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[4-(methanesulfonyl)-phenyl]-spiro[2H, 1 -benzopyran-2,4'-piperidine]; and

4-[(4-N,N-diethylaminocarbonyl)phenyl]spiro[2H, 1 -benzopyran-2,4'-nortropine]; or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

[0118] In other aspects, the disclosure is related to compounds of formula IV:

wherein:

Y² is a single bond or — [C(R^c)(R^d)]_k — ; each R^c, R^e, and R^f is independently H or alkyl; each R^d is independently H, alkyl, or aryl; W² is aryl, alkaryl, heterocycloalkylaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl; R²³ and R²⁴ are each independently H, alkyl, alkenyl, alkynyl, or aryl, or R²³ and R²⁴ when taken together with the atoms through which they are connected, form a 4- to 8-membered cycloalkyl or heterocycloalkyl ring; Z is -N(R²⁵)-, — C(=O)— , -CH(OH)-, — CH(N(R^c)(R^d))— , or —O-; R²⁵ is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, or R²³ and R²⁵ when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring, or R²⁴ and R²⁵ when taken together with the atoms through which they are connected, form a 4- to 8-membered heterocycloalkyl ring; each k is independently 1, 2, or 3; p is 0, 1, 2 or 3; s is 0, 1, 2 or 3, provided that the sum of p and s is <4; A² and B² are each independently H, fluoro, or alkyl, or together form a double bond or — CH₂ — ; G is H or alkyl; X² is — C(R^c)(R^d)— , — O— , -S-, — S(=O)— , — S(=O)₂— , — C(=O)— , — CH(OH)- or — N(R²⁶)-; R²⁶ is H, alkyl, cycloalkyl, — (CH₂)-alkenyl, — (CH₂)-alkynyl, aryl, — C(=O)R^d, or — S(=O)₂R^d; and J² forms a 6- to 10-membered aryl or a 5- to 10- membered heteroaryl ring when taken together with the carbon atoms to which it is attached; provided that when: (a) J² taken together with the carbon atoms to which it is attached forms a 6- to 10-membered aryl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, -SH, — C(=O)— H, — S— C_1-4alkyl, — NHS(=O)₂— C_1-4 alkyl, — NHS(=O)₂— H, — N(C_M alkyl)S(=O)₂— H, C_I_₄ alkyl, and C_1-4 alkoxy, the latter two optionally substituted with one or more halogens or with C_1-4 alkoxy; W² is phenyl substituted with 0-3 groups selected from the group consisting of: halogen, cyano, hydroxy, C_1-6 alkyl optionally substituted with one or more halogens, C_1-6 alkoxy optionally substituted with one or more halogens or with C3-6 cycloalkyl, C₂_6 alkenyloxy, C₂_6 alkynyloxy, C3-6 cycloalkyloxy, C₆-I₂ aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, heterocycloalkyl substituted with alkoxy, -SH, -S-C_1-4 alkyl, -NH₂, — N=C(aryl)₂, — N(H)C_1-4 alkyl, — N(C_1-4 alkyl)₂, — OS(=O)₂ — C_1-4 alkyl optionally substituted with one or more halogens, — OS(=O)₂ — C₆-I₂ aryl optionally substituted with C_1-4 alkyl, — NHS(=O)₂ — C_1-4 alkyl, — N(C_L4 alkyl)S(=O)₂— C_1-4 alkyl, — NHS(=O)₂— H, and -N(C_1-4 alkyl)S(=O)₂— H; p and s are each 1 , R^e, R^f, R²³, R²⁴, and G are each H, A² and B² together form a double bond, Y² is a single bond; and X² is — O — ; then Z is other than:

wherein t is an integer from 1 to 20; and provided that when: (b) J² taken together with the carbon atoms to which it is attached forms a phenyl ring substituted with 0-3 groups selected from the group consisting of: halogen, hydroxy, — S — C_1-4 alkyl, C_1-4 alkyl, and C_1-4 alkoxy, the latter two optionally substituted with one or more halogens or with C_1-4 alkoxy; W² is unsubstituted naphthyl, or phenyl substituted with 0-3 groups selected from the group consisting of: halogen, C_1-6 alkyl, C_1-6 alkoxy, phenyl, phenoxy, 1,3-benzodioxazolyl, or 2,2- difluoro-1,3-benzodioxazolyl fluoro, — NH2, — N(C 1-4 alky 1)2, and pyrrolyl; p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B 2 together form a double bond, Y2 is a single bond; and — X2 is — O — ; then Z is other than:

and provided that when: (c) J2 taken together with the carbon atoms to which it is attached forms unsubstituted phenyl, W² is phenyl substituted with 0-3 groups selected from the group consisting of: fluoro, hydroxy, C 1-6 alkoxy optionally substituted with one or more fluoro, C2-6 alkenyloxy, and — S — C 1-4 alkyl, p and s are each 1, Re, Rf, R23, R24, and G are each H, A2 and B2 together form a double bond, Y2 is a single bond; and X2 is — O — ; then Z is other than:

and provided that when: (d) J2 taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with:

then Z is other than — N(R25) — or — CH(NH2) — ; or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide thereof.

[0119] In certain embodiments of compounds of formula IV, Y² is a single bond.

[0120] In some embodiments of compounds of formula IV, R^c, R^e, and R^fare each independently H or lower alkyl; H or C₁-C₃ alkyl; H or methyl; or each is H. In some embodiments, at least one of R^c, R^e, and R^f is H. [0121] In other embodiments of compounds of formula IV, each R is independently

H, alkyl, or phenyl, the later two optionally substituted; H, alkyl, or unsubstituted phenyl; H or alkyl; H or methyl; or H.

[0122] In certain embodiments of compounds of formula IV, W² is aryl, alkaryl, heteroaryl, alkylheteroaryl, heteroarylaryl, or alkylheteroarylaryl, each of which is optionally substituted; W² is aryl, alkaryl, heteroaryl, or heteroarylaryl, each of which is optionally substituted; W² is phenyl, pyridyl, tetrazolylphenyl, benzothienyl, benzofuranyl, thienyl, furanyl, indolyl, thiazolyl, pyrimidinyl, or diazolyl, each of which is optionally substituted.

[0123] As noted above, the ring systems in W² are optionally substituted. In some embodiments, the ring systems in W² are optionally substituted with at least one of alkyl, aryl, hydroxyl, carboxyl, N,N-dialkylaminocarbonyl, — S(=O)₂ — N(alkyl)₂, — N(H)S(=O)₂- alkyl, and — N(alkyl)C(=O)-alkyl. In some embodiments, W² is:

wherein W² is optionally substituted with at least one of alkyl, aryl, hydroxyl, carboxyl, N ,N- dialkylaminocarbonyl, — S(=O)₂— N(alkyl)₂, — N(H)S(=O)₂-alkyl, and — N(alkyl)C(=O)- alkyl; and L is H or alkyl.

[0124] In some embodiments of compounds of formula IV, R²³ and R²⁴ are each independently H or alkyl, alkenyl, alkynyl, or aryl, each of the latter four groups being optionally substituted; R²³ and R²⁴ are each independently H, alkyl, alkenyl, or alkynyl; R²³ and R²⁴ are H; R²³ and R²⁴ are each independently H, alkyl, alkenyl, or alkynyl; R²³ and R²⁴ are each independently H, C₁-C₃ alkyl, C₂-C₃ alkenyl, or C₂-C₃ alkynyl; R²³ and R²⁴ are each independently H, C₁-C₃ alkyl, or C₂-C₃ alkenyl; or at least one of R²³ and R²⁴ is H.

[0125] In certain embodiments of compounds of formula IV, Z is — N(R²⁵) — , —

CH(N(R^c)(R^d))— , or — O— ; or -N(R²⁵)-, -CH(OH)-, or — CH(N(R^c)(R^d)).

[0126] In some embodiments of compounds of formula IV, R²⁵ is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, aralkyl, or heteroarylalkyl, each of the latter seven groups being optionally substituted; or R²⁵ is H, alkyl, or aralkyl; H or alkyl; H or lower alkyl, H or methyl; or H.

[0127] In some embodiments of compounds of formula IV, k is 1.

[0128] In some embodiments of compounds of formula IV, p is 0, 1 or 2.

[0129] In some embodiments of compounds of formula IV, s is 0, 1, or 2.

[0130] In some embodiments of compounds of formula IV, the sum of p and s is 2 or

3.

[0131] In some embodiments of compounds of formula IV, A² and B² are each independently H, fluoro, or alkyl, or together form a double bond; each is independently H or alkyl, or together they form a double bond; each is independently H or lower alkyl, or together they form a double bond; or H or methyl, or together they form a double bond. In some embodiments of compounds of formula IV, A² and B² are each independently H, fluoro, or alkyl. Alternatively, A² and B² together form — CH₂ — .

[0132] In some embodiments of compounds of formula IV, G is H or lower alkyl; H or methyl; or H.

[0133] In certain embodiments of compounds of formula IV, X² is — C(R^c)(R^d) — , —

O— , -S-, — S(=O)— , — S(=O)₂— , or -N(R²⁶)-; — C(R^c)(R^d)— , — O— , or — S(=O)₂— ;— C(R^c)(R^d)— or —O-; or —O-.

[0134] In some embodiments of compounds of formula IV, R²⁶ is H or alkyl; H or lower alkyl; H or methyl; or H. [0135] In some embodiments of compounds of formula IV, J forms a 6- to 10- membered optionally substituted aryl ring when taken together with the carbon atoms to which it is attached; optionally substituted phenyl or optionally substituted naphthyl; or optionally substituted phenyl.

[0136] In certain embodiments, the compounds of formula IV have the structure according to formula V:

[0137] In certain embodiments, the compounds of formula IV have the structure according to formula VI:

wherein A² and B² are each independently H, fluoro or alkyl.

[0138] In certain embodiments, the compounds of formula IV have the structure according to formula VII:

[0139] In certain embodiments, the compounds of formula IV have the structure according to formula VIII:

wherein A² and B² are each independently H, fluoro or alkyl.

[0140] In certain embodiments, the compounds of formula IV have the structure according to formula IX:

[0141] In certain preferred embodiments, the compounds of formula IV have the structure according to formula X:

[0142] In certain preferred embodiments, the compounds of formula X have the structure according to formula XI:

[0143] In certain embodiments, the compounds of formula X have the structure according to formula XII:

wherein:

Q¹ and Q² are each independently H, halo, alkyl, hydroxyl, alkoxyl, cycloalkyl substituted alkoxyl, aminocarbonyl, — S(=O)₂-alkyl, — S(=O)₂— N(H)alkyl, — S(=O)₂— N(H)cycloalkylalkyl, or — N(H)S(=O)₂-alkyl. [0144] In certain other embodiments, the compounds of formula XII have the structure according to formula XIII:

[0145] In certain embodiments of compounds of formula IV, the compound is selected from the group consisting of:

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[6-fluoro-2H,l-benzopyran-2,4'- piperidine];

4- [(2-N,N-diethylaminocarbonyl)pyrid-5 -yl] -spiro [5 -methoxy-2H, 1 -benzopyran-2,4'- piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[5-hydroxy-2H,l-benzopyran-2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,l-benzopyran-2,4'-azepane];

4- [(4-N,N-diethylaminocarbonyl)phenyl] -spiro [6-cyclopropylmethylaminosulfonyl-2H, 1 - benzopyran-2,4'-azepane];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[3,4-dihydro-2H,l-benzopyran-2,4'- piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[1,2-dihydronaphthalene-2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl-2-hydroxy)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine]; 4-[(4-N,N-diethylaminocarbonyl-3-hydroxy)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4- [(4-N,N-diethylaminocarbonyl)phenyl] -3 -methyl-spiro [2H, 1 -benzopyran-2,4'-piperidine] ;

4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-cyclopropylmethoxy-2H,l-benzopyran- 2,4'-piperidine];

4- [(2-N,N-diethylaminocarbonyl)pyrid-5 -yl] -spiro [-6-cyclopropylmethoxy-2H, 1 -benzopyran- 2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-aminocarbonyl-2H,l-benzopyran-2,4'- piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-propylaminosulfonyl-2H,l-benzopyran- 2,4'-azepane];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-methanesulfonyl-2H,l-benzopyran-2,4'- azepane];

4-[(2-N,N-diethylaminocarbonyl)pyrid-5-yl]-spiro[3,4-dihydro-2H,l-benzopyran-2,4'- piperidine];

4- [(2-N,N-diethylaminocarbonyl)pyrid-5 -yl] -spiro [6-fluoro-3 ,4-dihydro-2H, 1 -benzopyran- 2,4'-piperidine];

4-[(5-N,N-diisopropylaminocarbonyl)pyrid-2-yl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-ethylsulfonylamino-2H,l-benzopyran-2,4'- piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[6-methylsulfonylamino-2H,l -benzopyran- 2,4'-piperidine];

4- [(4-N,N-diethylaminocarbonyl)phenyl] -spiro [5 -methyl-2H, 1 -benzopyran-2,4 '-piperidine] ;

4-[4-(2H-tetrazol-5-yl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[4-(2-methyl-tetrazol-5-yl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine]; 4-[3-(2-(3-carboxyprop- 1 -yl)-tetrazol-5-yl)phenyl]-spiro[2H, 1 -benzopyran-2,4'-piperidine];

4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)phenyl]-spiro[2H,l-benzopyran-2,4'-piperidine];

4-[(4-N,N-diethylaminocarbonyl)phenyl]-spiro[2H,l-benzopyran-2,4'-(r-methyl-piperidine];

4-[(4-N,N-diethylaminosulfonyl)phenyl]-spiro[2H, 1 -benzopyran-2,4'-piperidine]; and

4-[(4-(N-methyl-N-(3-methylbutanoyl)-amino)phenyl]-spiro[2H,l-benzopyran-2,4'- piperidine];

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, and N-oxide thereof.

[0146] An exemplary delta opioid receptor agonist compound that can be used with the methods of the disclosure is ADL 5859, which has the following structure:

[0147] The chemical synthesis of ADL 5859 is described in Example 1 IA of U.S.

Patent Publication 2008/0102031, which is incorporated by reference herein in its entirety.

[0148] Also useful are delta opioid receptor antagonist compounds. Exemplary antagonists include, but are not limited to, naltrindole, or a 3-ether analog of naltrindole, or 17- cyclopropylmethyl-6, 7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'-indolomorphinan, or naltrindole analogues substituted in the indolic benzene moiety, or opioid diketopiperazines, or the indolomorphinan HS 378. Additionally useful therapeutic agents are mixed agonists compounds with high specificity for delta opioid receptors. A mixed agonist is a compound that can function as an agonist or antagonist depending on the physiological parameters. If a receptor is inactive, the mixed agonist will activate it; if the receptor system is highly activated, then a mixed agonist will decrease the level of activity. Useful exemplary mixed agonists comprise N-alkyl- and N,N-dialkyl-4-[alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1- piperazinyl] benzylj-benzamides (PMID:9288176); buprenorphine; and the 1,3,5- trisubstituted 1,2,4-triazoles [PMID: 19646882 ].

[0149] Compounds useful in the practice of this disclosure can be formulated into pharmaceutical compositions together with pharmaceutically acceptable carriers for oral or sublingual administration in solid or liquid form, or for intravenous, intramuscular, subcutaneous, transdermal, or topical administration. Pharmaceutical compositions in gaseous form can be used for administration by inhalation.

[0150] Such pharmaceutically acceptable carriers for oral administration include capsules, tablets, pills, powders, troches, and granules. In the case of solid dosage forms, the carrier can include at least one inert diluent such as sucrose, lactose or starch. Such carriers can also include additional substances other than diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, troches and pills, the carrier can also include buffering agents. Carriers, such as tablets, pills and granules, can be prepared with enteric coatings on the surfaces of the tablets, pills or granules. Alternatively, the enteric coated compounds can be pressed into tablets, pills, or granules. Pharmaceutically acceptable carriers include liquid dosage forms for oral administration, e.g. emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening or flavoring agents, and the like.

[0151] Sublingual dosage forms provide transmucosal delivery of an active agent, e.g., a CORM, primarily through the oral epithelium beneath the tongue. Sublingual dosage forms are known in the art and can include, but are not limited to, lozenges, tablets, oral dissolving/disintegrating tablets (ODTs), muco-adhesive tablets (including muco-adhesive films), fast-melt dissolving tablets (including fast-melt dissolving films), orally disintegrating dosage forms, troches, and the like. For sublingual administration, dosage forms may be formulated which are rapidly soluble when introduced into the oral cavity. For example, dosage forms with dissolution time of about two minutes or less are provided. Rapid dissolution of the dosage form which is necessary to facilitate sublingual absorption may be achieved by selection of an appropriate method of tablet manufacture. [0152] Dosage forms for the topical or transdermal administration of a compound according to the disclosure include, but are not limited to, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0153] Pharmaceutically acceptable carriers for topical administration include, but are not limited to, DMSO, alcohol or propylene glycol and the like that can be employed with patches or other liquid retaining material to hold the medicament in place on the skin. Approaches based on nanoparticles, nanoencapsulates and the like are also useful for the protection of the active principle and its slow release in the organism or specific tissues.

[0154] Pharmaceutical compositions of the disclosure for parenteral administration comprise compounds according to the disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. Pharmaceutically acceptable carriers for intravenous administration include solutions containing pharmaceutically acceptable salts or sugars. Pharmaceutically acceptable carriers for intramuscular or subcutaneous injection include salts, oils, or sugars.

[0155] For inhalation, the CORM can be dissolved in a biologically-compatible excipient (e.g., water or saline). Alternatively, the CORM is inhaled in solid or liquid form, the particles or droplets are deposited throughout the respiratory system, with larger particles or droplets tending to be deposited near the point of entry (i.e., the mouth or nose) and smaller particles or droplets being carried progressively farther into the respiratory system before being deposited into the trachea, bronchi, and finally the alveoli. (See, e.g., Hounman & Morgan, "Particle Deposition," Ch. 5 in Respiratory Defense Mechanisms, Part 1, Marcel Dekker, Inc., NY; ed. Brain et al., 1977, p. 125). A particle/droplet size of 10 μm or less is useful.

[0156] The pharmaceutically acceptable carriers and compositions of the disclosure are formulated into unit dosage forms for administration to the patients. The dosage levels of active ingredients (i.e., compounds of the disclosure) in the unit dosage may be varied so as to obtain an amount of active ingredient that is effective to achieve a therapeutic effect in accordance with the desired method of administration. The selected dosage level therefore mainly depends upon the nature of the active ingredient, the route of administration, and the desired duration of treatment. If desired, the unit dosage can be such that the daily requirement for an active compound is in one dose, or divided among multiple doses for administration, e.g. two to four times per day.

[0157] In lieu of, or in addition to, employing CORMs, pharmaceutical compositions comprising CO can be used to deliver a therapeutically effective amount of CO to a patient suffering from sensations of suffocation. For example, compositions comprising CO in gaseous form may be used to deliver therapeutically effective amounts of free carbon monoxide. Compressed CO gas useful for the presently described methods can be obtained commercially.

[0158] It is well known that CO is toxic when it reaches high levels in the environment and in the blood. The toxicity of CO is due to its ability to bind to the heme group of hemoglobin, the oxygen-carrying molecule in human blood. Hemoglobin that is associated with CO is referred to as carboxyhemoglobin (COHb). Because CO's affinity to bind with hemoglobin is 250 times greater than that of oxygen, relatively low airborne concentrations and long exposure times can result in substantial COHb concentrations in the blood. As COHb levels increase, less hemoglobin is available for the transport of oxygen. The severity of symptoms due to CO exposure depends mainly on the concentration of CO and the length of exposure time. COHb saturations of about 0.5% to 3% can be found in nonsmoking adults and levels of about 5 to 6% have been reported in smokers and in patients with hemolytic anemias. The symptoms of CO poisoning are usually only seen at COHb levels above about 10%. As used herein, "about" means a numeric value having a range of ± 10% around the cited value.

[0159] However, the above described toxicity of CO occurs at levels that are far above the levels required to achieve therapeutic effects. Therapeutically effective dose levels are determined in animals for CO and for representative compounds from each class of CORM. The lower level limits of COHb concentration determined for non-smokers are used to provide a margin of safety for the determination of CO toxicity, since smokers are known to become partially insensitive to the acute toxicity of CO. Although CO is generated at the target tissue, some of the CO generated binds to hemoglobin in red blood cells. Thus, dose finding studies are guided by measurement of COHb levels in the blood. Dose levels of the compounds described in the present disclosure are such that no significant rise in COHb levels is observed. However, in some applications a transient rise in COHb levels up to about 10% may be tolerated. This level of COHb is not associated with any symptoms.

[0160] Methods for the measurement of COHb levels in the blood are well known and are being used on a regular basis in diagnostic laboratories. For example, CO may be measured in exhaled air (end-tidal measurements, i.e., at the end of the exhalation phase) via infrared methods similar to those used to measure carbon dioxide. These measurements may be calibrated with known concentrations of CO via standard laboratory methods.

[0161] CORMS are administered in a dosage ranging between about 5 mmo I/day and

25 mmo I/day depending on the nature of the compound and its molar CO content. In some embodiments, the therapeutically effective amount of CORM administered is from about 0.001 mg/kg body weight to about 20 mg/kg body weight of the mammal, for example, from about 0.01 mg/kg body weight to about 1 mg/kg body weight of the mammal, from about 0.1 mg/kg body weight to about 10 mg/kg body weight of the mammal, from about 0.03 mg/kg body weight to about 0.3 mg/kg body weight of the mammal, from about 0.3 mg/kg body weight to about 3.0 mg/kg body weight of the mammal, or about 1.0 mg/kg body weight of the mammal.

[0162] In some embodiments, the concentration of CO in the therapeutic gas is at least about 1 ppm, at least about 10 ppm, from about 1 ppm to about 10 ppm, from about 1 ppm to about 20 ppm, from about 5 ppm to about 25 ppm, or from about 10 ppm to about 50 ppm. In some embodiments, the concentration of CO in the therapeutic gas is from about 1 ppm to about 50 ppm. In some embodiments, the concentration of CO in the therapeutic gas is no more than about 50 ppm, which has been determined to be the level at which healthy adults experience toxicity when exposed for periods longer than eight hours (Bye et al., (2008) Inhalation Toxicol., 20: 635-546). Therapeutic gas is provided to a patient for a least about 10 seconds to at least about 5 minutes. It is within the purview of the skilled physician to adjust the inhalation period and concentration as necessary. For example, lower concentrations of CO can be used for longer periods, or higher concentrations can be used for shorter periods. Dosages can be extended or repeated as needed. In some embodiments, CO can be used at a concentration of about 1-50 ppm for indefinite periods of time, and higher concentrations for intermediate periods (such as an hour).

[0163] For example, a patient in an intensive care environment who is being mechanically ventilated may be monitored for at least 10 minutes before administration of CO. Mechanical ventilation parameters such as positive end expiratory pressure, respiratory rate, pulmonary artery pressure, end-tidal volume CO₂ partial pressure and pulse oximetry oxygen saturation may be recorded at 10 minute intervals as CO concentration is increased from an initial concentration of 1 ppm. Patients who are alert and responsive may be asked to indicate their respiratory distress on a 10 cm visual analog scale, with the extremes of 0 and 10 cm indicating no distress and extreme distress, respectively. The desired outcome is optimization of ventilator parameters, such that oxygenation saturation exceeds 90% with minimal increments of positive end expiratory pressure, minimization of patient over- breathing (breathing faster than the ventilator), and decrease of subjective respiratory distress to values below 3.0 cm. The primary guide is the patient's report of distressing air hunger, resulting in requests for more relief; objective indicators such as oxygen saturation are safety measures rather than efficacy measures, since patients may continue to be extremely distressed despite adequate oxygenation.

[0164] The dose is controlled so that the patient's carboxy-Hb does not exceed about

20% of total Hb. Alternatively, the CO is provided at a relatively higher concentration, particularly where the patient inhales the therapeutic gas for only a brief period of time before switching back to air or oxygen. When the therapeutic gas includes CO, a useful benchmark is a concentration of CO that produces 2% to 10% carboxy-Hb in the patient's blood, as measured by conventional means. The therapeutic gas provided for inhalation may also include oxygen (e.g., approximately 20% oxygen, such as in air, and up to nearly 100% oxygen).

[0165] Therapeutic amounts of CO gas can be administered to a patient through the use of commercially available devices, such as a mask-breathing circuit or a portable inhaler device. Examples of suitable inhaler devices that could be adapted for the methods of the disclosure are described in WO 92/10228, and in U.S. Patent Nos. 5,485,827, 5,396,882, 4,667,668; 4,592,348; 4,534,343; and 4,852,561. Other useful inhaler devices are described in the Physicians' Desk Reference (Edward R. Barnhar, Publisher, 2005). Generally, suitable inhaler devices are portable, i.e., less than 5 kg, or less than 1 kg, and may be of a design similar to those inhalers currently available for the treatment of asthma attacks. The device contains either or both of (a) pressurized CO gas, and (b) a CO releasing molecule. Typically, such a device includes a pressurized gas containing at least 1 ppm, at least 5 ppm, at least 40 ppm, or at least 80 ppm CO. The concentration of CO in the pressurized gas can be relatively high, e.g., 160 ppm, 300 ppm, 500 ppm, or 1000 ppm. Concentrations as high or even higher than 1500 ppm or 2000 ppm may also be used. If desired, the device can contain a mixture of pressurized CO gas and either an inert gas such as N₂, or a liquid propellant such as a fluorocarbon, e.g. , freon.

[0166] Prior to administering the therapeutic gas to the patient, the patient's blood can be analyzed in order to establish a baseline against which the CO-treated blood can be compared. Typically, a 10 ml sample of blood is drawn into a heparinized syringe, and the hemoglobin, hematocrit, oxygen saturation, and/or methemoglobin saturation measured. The oxygen dissociation curve (ODC) and/or P₅₀ of the patient's hemoglobin is measured before the therapeutic gas is inhaled. Any or all of these parameters can be measured again following inhalation of the therapeutic gas to provide a measure of the therapeutic effectiveness of the inhaled gas. If desired, the patient's blood oxygen saturation can be monitored by pulse oximetry while the patient breathes the therapeutic gas. Additional blood samples can be drawn over time, as the patient continues to breathe the therapeutic gas.

[0167] In some embodiments, the disclosure provides a pharmaceutical composition for treating sensations of suffocation in a patient, the composition comprising a pain-relieving compound, and at least one other therapeutic agent. The at least one other therapeutic agent may include, but is not limited to, one that is useful for treating panic attacks, panic disorder, a condition related to panic disorder, or dyspnea.

[0168] The at least one other therapeutic agent is also administered in an amount effective in reducing the symptoms on the disease or disorder, whether used additively or synergistically in combination with the pain-relieving compound. The at least one other therapeutic agent can be administered separately from the pharmaceutical compositions described herein, or it can be administered simultaneously and/or successively with the pharmaceutical compositions described herein. [0169] Effective amounts of the at least one other therapeutic agent are known to those skilled in the art. The at least one other therapeutic agent's optimal effective amount range can be determined using references such as Goodman and Gilman 's The Pharmacological Basis of Therapeutics (Macmillan Publishing, 2005). In some other cases, the patient in need of treatment is being treated with at least two other therapeutic agents.

[0170] The at least one other therapeutic agent can be, but is not limited to, an antidepressant agent, a selective serotonin reuptake inhibitor (SSRI), a benzodiazepine, and a beta-blocker. Antidepressants are useful therapeutic agents commonly prescribed for treating both depression and anxiety disorders. Antidepressants may begin to alter brain chemistry after one dose but generally take a longer period of time to take full effect. Useful antidepressant agents include, but are not limited to, doxepin, clomipramine, nortriptyline, citalopram, trazodone, venlafaxine, amitriptyline, escitalopram, fluvoxamine, phenelzine, desipramine, tranylcypromine, paroxetine, fluoxetine, mirtazapine, nefazodone, trimipramine, imipramine, bupropion, and sertraline. These are commercially available drugs.

[0171] SSRIs are a type of antidepressant that operate by altering the levels of the neurotransmitter serotonin in the brain. SSRIs generally have fewer side effects than older antidepressants. Useful selective serotonin reuptake inhibitors include, but are not limited to, paroxetine, sertraline, fluoxetine, citalopram, escitalopram, and fluvoxamine. These are commercially available.

[0172] Benzodiazepines are potent agents that are useful for combating anxiety with few side effects other than drowsiness, and are generally prescribed for short periods of time. Useful benzodiazepines include, but are not limited to, clonazepam, alprazolam, and lorazepam. These are commercially available.

[0173] Beta-blockers are generally used to treat heart conditions, but are also useful for preventing the physical symptoms that accompany anxiety disorders. For example, when a feared situation can be predicted, a beta-blocker may be prescribed to keep the physical symptoms of anxiety under control. Useful beta-blockers include, but are not limited to, propranolol, which is commercially available. [0174] Before any humans are exposed to test materials, studies in mice, rats and nonhuman primates are conducted to better delineate the risks and the potential benefits to patients.

[0175] These studies are concerned with control of respiration and perceived suffocation. Mouse respiratory physiology is well known and pilot data clearly show that the mouse model will allow rapid screening of the effects of pharmacological manipulations. Transgenic animals with delta receptor knock-outs exist in mice, thus, the use of mice is well justified for these studies. Rats are also studied to assess toxicity in a second species with sufficient statistical power and to facilitate translation of imaging approaches from humans to rodents. The study of non-human primates is justified.

[0176] The proposed human phase I study is limited to healthy nonpregnant adults who are lifelong nonsmokers between the ages of 21 and 45, with a normal physical exam, EKG, chest x-ray and spirometry. Phase II and phase III studies are drawn from the cohort of individuals enrolled in the NYU Lung Cancer Biomarker C₆nter for the Early Detection of Cancer directed by clinical PD/PI Rom. Eligible participants have a diagnosis of COPD and prominent dyspnea symptoms but without significant hypoxia and without heart disease. About 50 individuals with COPD participate.

[0177] Participants in the proposed work under this project provide physiological and lab measures (EKG, oxygen and COHb saturations, end-tidal CO₂, and blood for cardiac enzymes); structural and functional imaging data; cognitive performance data; and ratings of dyspnea and well-being. Recruitment of healthy volunteers is carried out in the community through announcements and notices as approved by the IRB. Patients with COPD are recruited from the NYU Lung Cancer Biomarker C₆nter for the Early Detection of Cancer by PD/PI Rom, as approved by the IRB.

[0178] Administration of all agents which modulate the asphyxial alarm system is carried out in the NYU/Bellevue Pulmonary Function Lab where participants are closely monitored. Participation in trials is preceded by medical evaluation excluding individuals with cardiac disease or history of angina. The study subjects have their oxygen saturation and blood pressure monitored during the procedure, and subsequently until the subject is fully alert, or for 2 hours after the procedure, whichever is longer. Subjects receive supplemental oxygen as needed to prevent hypoxemia. [0179] The disclosure will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the disclosure.

EXAMPLES

EXAMPLE 1 Sensitivity of Mice Lacking Delta Opiate Receptors to CO?

[0180] The mammalian suffocation alarm system is exquisitely sensitive to increased plasma levels Of CO₂ and its metabolic equivalents. Organisms respond initially to increased CO₂ levels by increasing the rate and depth of respiration. When the inhaled air contains increased concentrations of CO₂, then such respiratory maneuvers are ineffective. In humans, the persistent sensation of imminent suffocation which results from breathing 5% CO₂ is a useful validated biomarker of the propensity to develop panic attacks and panic disorder.

[0181] The effects of various carbon dioxide (CO₂) concentrations were tested on mice that lack specific opiate receptors in order to test modulation of the suffocation alarm system by delta opioid receptors (DOR). Oprdl^tmlKff/Oprdl^tmlKff mice were obtained from Jackson Labs (JAX; Bar Harbor, ME). These mice, derived from 129/Sv * C57BL/6, are homozygous for a mutant DOR allele which results in absence of the DOR in brain. The control mice are JAX 000664 C57BL/6J. Young adult mice or juvenile mice of either sex can be tested in the studies. The DOR knockout (DOR-) mice exhibit increased anxiety, depressive-like behavior, and increased ethanol self-administration. Increasing concentrations of CO₂ have significantly stronger effects on respiratory dysregulation in comparison to WT mice.

[0182] Fig. 1 shows the results of a study using mature C57BL/6 mice (n=4). The mice were placed in a whole body plethysmograph (Buxco) that allowed noninvasive monitoring of respiration rate and tidal volume from freely moving animals and online gas exchange. Following 15 min adaptation period, normal breathing air was switched to a mix containing 5% CO₂ for 2 min. Normal air was reinstated for 5 min and the cycle repeated three times. In response to 5% CO₂, mice increased both respiration rate and volume 10-15% (Fig. 1). The plethysmograph incorporates a gas mixing chamber that allows multiple gas mixtures to be sequentially or simultaneously tested, thus allowing the effects of CO on CO₂ induced respiratory responses to be assessed as proposed. In addition, the study can include gas analysis allowing comparison of gas (O₂ and CO₂) concentrations downstream of the subject to those upstream of the subject. Differences due to respiration can be used to calculate VO₂, VCO₂, and metabolic rate.

[0183] In another study, 30 DOR knockouts mice are compared to 30 WT mice to examine effects of varying CO₂ concentrations (3% to 5%) on tidal volume. CO₂ is administered into a full-body plethysmograph, or a head vs. body divided or similar hermetically sealed chamber in which calibrated concentrations of gas can be maintained. Orthogonal video recording may also be used to quantify tidal volume and respiratory rates. Test periods are determined on the basis of initial experiments designed to last 30 min. Standard methods available commercially, e.g., in Expose (SCIREQ, Scientific Respiratory Equipment Inc.) may be used to quantify tidal volume (ml) are used in order to assess change from room air to elevated CO₂ (3% or 5%) as strains of mice differ.

[0184] DOR- mice may be more sensitive to elevated CO₂ levels and show significantly increased initial tidal volumes. By analogy with human responses, after a period of ineffective compensation (since increased tidal volume will not resolve the hypercarbia), DOR- mice transition to a panting respiratory pattern characterized by rapid shallow breathing. The overall pattern of respiratory responses is evaluated as well as specific endpoints of tidal volume change at baseline, 5 min, 10 min, and 30 min. Mean tidal volumes in mice typically range between 0.3 mL to 0.5 mL, with respiratory rates of 3 to 5 breaths per second. Initial changes of 20% to 30% in tidal volume and later increases in respiratory rate of 20% to 50% over baseline occur under the condition of 5% CO₂.

[0185] KO mice lacking the mu-opioid receptor (MOR-) are also obtained from JAX

(Strain name B6.129S2 — Oprml^tmlKff/J, Stock No. 007559) and their respiratory responses to elevated CO₂ levels tested. Kappa-opioid receptor KO mice (KOR-) are also compared to DOR-, MOR-, and WT mice to determine the specificity of sensitivity to elevated CO₂ concentrations.

[0186] Both opioid receptor KO mice and WT mice are then tested with therapeutically effective amounts of CO and/or other specific therapeutic anti-panic agents, such as selective serotonin reuptake inhibitors or non-specific propranolol. CO is administered as a gas in a phethysmographic or similar chamber, with concentrations selected to bracket potentially therapeutic concentrations by targeting tissue concentrations of 25 ppm for one hour before testing in 5% CO₂ and measuring tidal volume and respiratory rates. DOR- mice have exaggerated responses to elevated CO₂ exposure relative to WT mice and to MOR- and KOR- mice. The SSRIs fluoxetine (5 mg/kg, 10 mg/kg, 20 mg/kg, and 40 mg/kg, s.c), paroxetine (5 mg/kg, 10 mg/kg, and 20 mg/kg, s.c), or sertraline (5 mg/kg, 10 mg/kg, and 20 mg/kg, s.c), considered specifically anti-panic, are compared to placebo or nonspecific psychotropic agents, e.g. propranolol, haloperidol. SSRIs and other psychotropic agents are administered daily for two weeks prior to CO₂ challenge.

[0187] Mice (n=3) were tested with a delta i_/2 opioid receptor antagonist, Naltrindole.

Mice were either injected systemically with saline or with Naltrindole (0.1 mg/kg) in a within-animal, counterbalanced design. Fig. 2 shows that Naltrindole injected mice showed a strong potentiation of respiratory rate response to 5% CO₂ compared to controls. The potentiation of the rate response was not accompanied by potentiation of the volume response, suggesting a panting mode of respiration in the Naltrindole-injected mice. In addition, the Naltrindole mice recovered more slowly from the CO₂ challenge than controls. Slow respiratory recovery from lactate and CO₂ challenges in panic disorder patients has been repeatedly reported. DOR- and MOR- mice are then tested with differing amounts of Naltrindole to confirm the increase in CO₂ sensitivity produced by the specific delta opioid receptor antagonist.

EXAMPLE 2 Rat Studies

[0188] Ninety rats are tested per year for the first 3 years as described above for mice.

This number of animals is needed to obtain sufficient statistical power to minimize type II errors of missing toxicity.

EXAMPLE 3 Primate Studies

[0189] Five young, adult rhesus macaques are studied. These studies are justified because of the importance of carefully assessing potential risks in a more closely related species prior to administering potentially toxic molecules to healthy volunteers and to patients. Macaques are anesthetized as required for all distressing procedures with the exception of experiments requiring exposure to various concentrations of CO₂ which are designed to produce dyspnea. The experience of dyspnea is not in and of itself injurious. Animals are provided with supplemental oxygen whenever required to prevent hypoxia so as to avoid confounding specific effects of CO administration.

EXAMPLE 4 Treatment of Human Patients with CO

[0190] A FDA compassionate use exemption is sought for administration of CO to patients suffering from ARDS, COPD, cancer, or congestive heart failure. These patients are very often most distressed by severe dyspnea that only responds to obtunding levels of morphine. Such severe treatment refractory dyspneic patients are most likely to benefit from the effects of CO on the suffocation alarm system. Several dyspnea scales are available to the skilled physician for identifying severe treatment refractory dyspneic patients. See, e.g., Hajiro et al, (1998) Am. J. Respir. Crit. Care Med.; 158:1185-1189.

[0191] FDA "compassionate use" exemptions refer to the provision of investigational products to patients outside of an ongoing clinical trial. Specific access programs with compassionate use exemptions include Treatment Investigational New Drugs (Treatment INDs, see 21 C.F.R. §31234{a-b)) and single-patient treatment INDs.

[0192] The concentration of CO necessary to minimize the use of palliative doses of opiates such as morphine is determined initially by pilot studies showing apparent efficacy followed by controlled comparisons of CO with room air administration. Application is made to the Food and Drug Administration and to the respective Institutional Review Board to administer CO to 30 consecutive patients who meet the following inclusion criteria: (1) diagnosis of terminal illness with life expectancy of six months or less, (2) competent to provide informed consent, (3) marked to severe degrees of respiratory distress requiring continuous administration of morphine or other opioid agents, (4) expressed desire for greater alertness or residual respiratory distress despite maximal opioid administration.

[0193] Initial administration of CO is single blind (i.e., the patient and family members are unaware of whether CO or room air, or oxygen without CO is being administered, but the physician and medical team are aware) until apparent therapeutic benefits are obtained or until end-points are reached. End-points include any of the following: CO concentration of 50 ppm, decreased pulse oximetry saturation to levels below 85% despite oxygen administration greater than 5 L/minute, and increase in subjective respiratory distress greater than 1.0 cm from lowest recorded level on two consecutive 10 minute intervals. A CO concentration between 1 and 50 ppm is selected on the basis of the initial titration as providing the best balance of decreased respiratory distress (increased alertness or decreased need for opioid administration, on the one hand, and lowest CO dose on the other) and such dose or doses are pseudorandomly interspersed with 0 ppm CO for up to 4 hrs at a time. Presentation of 0 ppm CO (inactive phase) and the non-zero concentration being tested is randomly assigned, except that no phase is repeated more than twice in a row. Desired outcomes are optimization of ventilator parameters, such that oxygenation saturation exceeds 90% with minimal increments of positive end expiratory pressure, minimization of patient over-breathing (breathing faster than the ventilator), and decrease of subjective respiratory distress to values below 3.0 cm. Another outcome is the length of time endured before the patient requests early termination of the current phase and initiation of the subsequent scheduled phase. This allows patients to minimize their respiratory distress if they are able to consistently detect a benefit from the non-zero CO phase.

[0194] Since CO is not detectable by odor or subjective sensation, this single blind comparison is facilitated. As the doses of morphine required to produce palliation differ widely depending on factors specific to each individual, including the degree of partial tolerance, the primary outcome measure is the change in total morphine requested by patients per eight-hour period. Dose ranges for CO and methods of administration are determined for each patient after initial pilot efforts to establish the dose range. Gaseous administration of CO is facilitated in cases in which patients are being ventilated by a mechanical ventilator, thus minimizing concerns about "second-hand" CO inhalation by staff members and visitors.

[0195] Alternatively, water-soluble CORMS, such as tricarbonylchloro(glycinato) ruthenium(II) (CORM-3) or sodium boranocarbonate (CORM-Al), commercially available from hemoCORM Ltd. (Middlesex, United Kingdom) are administered as described above. In all cases, expired concentrations of CO are measured via infrared methods.

EXAMPLE 5 Mouse Studies with Delta Opioid Recepter Antagonists

Methods

[0196] For testing, the animal was placed individually in a calibrated Buxco plethysmograph that was connected to one air tank containing normal air and another tank containing a 5% carbon dioxide mixture. These two tanks were connected with a Y shaped stopcock that allowed switching between the two tanks during the experiment. Airflow though the mixing chamber and plethysmograph was 2 LPM. Each animal was placed in the plethysmograph with normal air for a 15 min habituation period where its respiratory rate and tidal volume were recorded using Cambridge Electronic Design computer interface and Spike2 software. Animals were tested in 3 conditions in a randomly counterbalanced order with at least 10 days between each test. The conditions were: (1) Uninjected; (2) Injected with Saline, and (3) Injected with alprazolam. On days where the animal remained uninjected, a 2 min exposure to the 5% CO₂ air mixture followed the 15 min baseline. For the other two protocols, each animal was removed from the plethysmograph after the baseline period, lightly anesthetized with isoflurane and injected subcutaneously with either saline or alprazolam (0.3 mg/kg, Griebel et al., Neuropharmacology (1991) 34:1625-1633). After waking, the animal was placed back inside the plethysmograph and allowed to fully recover for 30 min in normal air before the 2 min exposure to the CO₂ mixture. A lO min recovery period with normal air followed the CO₂ exposure in all protocols. After the testing session, the animals were placed back in their home cages.

[0197] For each data file, changes in tidal volume and respiratory rate for the entire time span of the experiment using custom analysis scripts for Spike2 software (Cambridge Electronic Design). From this, 10 Hz readings were obtained for both respiratory rate and tidal volume from 30 sec before the CO₂ exposure to 2 min after CO₂ offset. Each data point was normalized ([x/mean]*100) to the mean values obtained during the 30 sec baseline period and expressed as percent of baseline. Single data points at the onset and offset of CO₂ were eliminated from the analysis due to transients that occurred in air pressure during the switch between tanks. The raw (non-normalized) baseline respiratory rate (Hz) and tidal volume (μL) measurements were also compared across animals and protocols.

Results

[0198] A single subcutaneous (S. C.) injection under light isoflurane anesthesia induced a long-lasting reduction in respiratory tidal volume and rate compared to uninjected controls which was detected in the baseline measures prior to initial CO₂ trial onset (FIGS. 3A-3B). There was no differential effect between WT and delta-knockouts in the response to injection. Genotype x injection ANOVA: Respiration Rate: main effect of injection, F(2,36) = 6.43, p < 0.01, interaction between genotype and injection F(2,36) = 1.23, N. S. Tidal Volume: main effect of injection, F(2,36) = 9.90, p < 0.001), interaction between genotype and injection, F(2,36) = 2.16, N.S.

[0199] Deltai-opioid receptor knock-out reduced tidal volume responses to 5% CO₂ challenge compared to controls. As shown in Figs. 4A - 4C, both genotypes (n=7/genotype) in the uninjected condition (Fig. 4A) showed elevated tidal volume responses during a 2 min exposure to 5% CO₂ relative to room air. There was no significant change in respiration rate during CO₂ in either genotype. The ratio of tidal volume to respiration rate during CO₂ exposure was also enhanced in both genotypes. The magnitude of the CO₂-induced change in tidal volume and ratio of tidal volume/rate was significantly reduced in the deltai -knockouts compared to wildtype. These results obtained in uninjected mice were replicated in the saline injection condition (Fig. 4B). Injection of the triazolobenzodiazepine alprazolam (0.3 mg/kg) 30 min prior to CO₂ challenge completely masked the genotype difference in tidal volume response to CO₂. Both genotypes (wildtype and delta opiate receptor knock-out) showed elevated tidal volumes and tidal volume/rate ratios during CO₂, but the difference between genotypes in CO₂ response was eliminated.

[0200] Significant repeated measures ANOVA's - Uninjected, tidal volume: F (21,252 = 1.78, p<0.05) for interaction of time X genotype; Uninjected, Ratio: F(21,252 = 2.43, p<0.01) for interaction of time X genotype; saline injected, tidal volume: F(21,252 = 1.94, p<.01) for interaction of time X genotype; saline injected, Ratio: F(21, 252 = 2.49, p<0.01) for interaction of time X genotype. Asterisks marked significant genotype differences based on post-hoc Fisher tests, p < 0.05.

EXAMPLE 6

Delta Opiate Receptor Effects on Respiratory Response to CO? and its Modulation by

Diazepam

Methods

[0201] Given that there is a reported differential efficacy between alprazolam and diazepam in treatment for panic disorder, the effects of diazepam were tested on response to CO₂ for comparison with the alprazolam data obtained in the same animals in Experiment 5, with n's = 4-6/group. Testing was performed on same transgenic deltai opioid receptor knockouts (Jackson Labs - Strain Name: B6A29S2-Oprdl^tmlκffβ) and WT controls as used in Experiment 5. All experimental manipulations and analyses were performed as described in Experiment 5. Individual mice received both saline and diazepam injections in a randomly counterbalance order with at least 10 days between treatments.

Results

[0202] As shown in Fig. 7 A, saline-injected delta-opiate knock-out mice had a reduced tidal volume response to 5% CO₂ challenge compared to saline-injected WTs, replicating the genotype effect found in Experiment 5. Delta knock-out mice show a reduced tidal volume response to 5% CO₂ challenge compared to wildtype controls. This difference was blocked by diazepam, (n's > 4/group). This difference in response to CO₂ between WT and delta-opiate receptor knockouts was eliminated by diazepam injections (1 mg/kg, David et al, Neuropsychopharmacology (2001) 24(3):300-318), similar to that observed with alprazolam injections (c.f. Fig 4C).

[0203] While both alprazolam and diazepam eliminated the difference between the

WT and knockout mouse CO₂ responses, they did so through slightly different mechanism. Compared to saline injections, alprazolam appeared to reduce WT response to CO₂ and enhance knock-out mouse responsiveness to CO₂, thus raising transgenic response levels toward WT levels (Fig. 4). In contrast, diazepam lowered wildtype response to CO₂ toward transgenic levels. There was no effect of diazepam on the CO₂ response of transgenic mice. This differential effect of alprazolam and diazepam on transgenic response to CO₂ may correspond to the differential clinical efficacy of these compounds on panic disorder.

EXAMPLE 7 Further CO? Testing

Methods

[0204] In a random subset of animals described above (n=3/genotype), the CO₂ exposure was extended to 15 min on a different test day, without injection, instead of the normal 2 min exposure. Finally for comparison, results are included of a preliminary pharmacology study using the same protocol but involving 5 different WT mice injected with: (1) saline; (2) the deltas receptor antagonist Naltrindole (0.1 mg/kg); (3) or a combination of Naltrindole (0.1 mg/kg) and the triazolobenzodiazepine Alprazolam (0.3 mg/kg). Results

[0205] As shown in Fig. 8, the results, though more variable, were the same, with the deltai -knockouts showing reduced tidal volume response compared to WT throughout the 15 min exposure.

[0206] These results are comparable to earlier findings using WT mice and pharmacological blockade of delta^ receptors with naltrindole (0.1 mg/kg). These results show a reduced tidal volume response in naltrindole injected mice compared to saline injected mice in response to 5% CO_2. This reduction was eliminated by co-injection with the triazolobenzodiazepine Alprazolam (0.3 mg/kg). These pharmacological findings were performed using "within animals, counterbalanced design," with at least 2-3 days between manipulations.

Equivalents

[0207] While the foregoing specification teaches the principles of the disclosure, with examples provided for the purpose of illustration, it will be appreciated by one skilled in the art from reading this disclosure that various changes in form and detail can be made without departing from the true scope of the disclosure.

Claims

Claimed is:

1. A method of treating the sensation of suffocation in a patient, the method comprising:

identifying a patient suffering from the sensation of suffocation; and

administering a therapeutically effective amount of a pharmaceutical composition to the patient, the pharmaceutical composition comprising a pain- relieving compound, the pharmaceutical composition reducing the sensation of suffocation in the patient.

2. The method of claim 1 , wherein the pain-relieving compound is selected from the group consisting of carbon monoxide (CO), a compound which releases CO in vivo, a delta opioid receptor agonist, a delta opioid receptor antagonist, a mixed delta opioid receptor agonist, and combinations thereof.

3. The method of claim 1 , wherein the sensation of suffocation is a result of panic attacks, panic disorder, a condition related to panic disorder, or dyspnea.

4. The method of claim 3, wherein the condition related to panic disorder is selected from the group consisting of agoraphobia, separation anxiety disorder, and major depression.

5. The method of claim 3, wherein the dyspnea is a result of respiratory distress.

6. The method of claim 1, wherein the pharmaceutical composition comprises CO.

7. The method of claim 2, wherein the pain-relieving compound comprises a moiety which releases CO in vivo.

8. The method of claim 2, wherein the pain-relieving compound is a delta opioid receptor agonist.

9. The method of claim 2, wherein the pain-relieving compound is a carbon monoxide- releasing molecule (CORM).

10. The method of claim 9, wherein the pain-relieving compound is a supramolecule aggregate comprised of cyclodextrin and an organometallic complex comprising CO.

11. The method of claim 2, wherein the pain-relieving compound is a delta opioid recveptor antagonist.

12. The method of claim 2, wherein the pain-relieving compound is a mixed delta opioid receptor.

13. The method of claim 1, wherein the pharmaceutical composition further comprises at least one other therapeutic agent.

14. The method of claim 13, wherein the at least one other therapeutic agent is useful for treating panic attacks, panic disorder, a condition related to panic disorder, or dyspnea.

15. The method of claim 2, wherein the pharmaceutical composition is a gaseous composition comprising CO at a concentration of about 1 ppm to about 50 ppm.

16. The method of claim 15, wherein the gaseous composition is provided to the patient for at least about 10 seconds, or for at least about 5 minutes.

17. A method for inhibiting suffocation signals emanating from the carotid body in a mammal, the method comprising contacting the mammal with a therapeutically effective amount of a pain-relieving compound, the compound inhibiting the suffocation signals.

18. A method of treating the sensation of suffocation in a patient suffering from panic attacks, panic disorder, a condition related to panic disorder, or dyspnea, the method comprising:

identifying a patient suffering from the sensation of suffocation as a result of panic attacks, panic disorder, a condition related to panic disorder, or dyspnea; and

administering a therapeutically effective amount of a pharmaceutical composition to the patient, the pharmaceutical composition comprising ADL 5859,

the pharmaceutical composition reducing the sensation of suffocation in the patient.