[go: up one dir, main page]

WO2025038666A2 - Composés et méthodes de traitement de la dépendance - Google Patents

Composés et méthodes de traitement de la dépendance Download PDF

Info

Publication number
WO2025038666A2
WO2025038666A2 PCT/US2024/042162 US2024042162W WO2025038666A2 WO 2025038666 A2 WO2025038666 A2 WO 2025038666A2 US 2024042162 W US2024042162 W US 2024042162W WO 2025038666 A2 WO2025038666 A2 WO 2025038666A2
Authority
WO
WIPO (PCT)
Prior art keywords
gatc
subject
effective amount
day
administering
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/042162
Other languages
English (en)
Other versions
WO2025038666A3 (fr
Inventor
Ian Jenkins
Robert TINDER
Vaishnavi Narayan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gatc Health Corp
Original Assignee
Gatc Health Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gatc Health Corp filed Critical Gatc Health Corp
Publication of WO2025038666A2 publication Critical patent/WO2025038666A2/fr
Publication of WO2025038666A3 publication Critical patent/WO2025038666A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates generally to small molecule therapeutics, more particularly, to compounds and methods of treating addiction.
  • opioid refers to a substance that acts on opioid receptors to produce morphine-like effects.
  • Opioids include the illegal drug heroin, synthetic opioids such as fentanyl, and pain relievers available legally by prescription, such as oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine, morphine and others.
  • Opioids can be classified according to their effect on opioid receptors. In this manner opioids can be considered as agonists, partial agonists and antagonists. In addition, opioids can be classified according to the type of opioid receptor at which they produce their effects. Classically, there are considered to be three opioid receptors. These receptors are all G-protein-coupled receptors, and were originally named mu (after morphine), delta (after vas deferens, the tissue within which it was first isolated) and kappa (after the first ligand to act at this receptor, ketocyclazocine). In 1996 the International Union of Pharmacology (IUPHAR) renamed the receptors OP1 (the delta receptor), OP2 (the kappa receptor) and OP3 (the mu receptor).
  • IUPHAR International Union of Pharmacology
  • the classical opioid receptors are distributed widely within the central nervous system and, to a lesser extent, throughout the periphery, occupying sites within the vas deferens, knee joint, gastrointestinal tract, heart and immune system, amongst others.
  • the stimulation of the differing opioid receptors produces a range of effects, which are often dependent upon the location of the receptor, along with analgesia.
  • Agonists binding to MOP receptors may cause analgesia, but also sedation, respiratory depression, bradycardia, nausea and vomiting and a reduction in gastric motility.
  • Activation of DOP receptors can cause spinal and supraspinal analgesia and reduce gastric motility
  • KOP receptor stimulation may produce spinal analgesia, diuresis and dysphoria.
  • Opioid agonist analgesics are used to treat moderate to severe, chronic cancer pain, often in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), as well as acute pain (e.g. , during recovery from surgery and breakthrough pain). Further, their use is increasing in the management of chronic, non-malignant pain.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Opioid dependence is a major health problem and long-term heroin use is connected to a substantially increased risk of premature death from drug overdoses, violence and suicide.
  • Well-known complications of opioids include the phenomenon of both physical and psychological dependence and addiction, which can in turn lead to opioid misuse, abuse and diversion. More than 70% of the illegal users obtain opioids by stealing them during pharmacy robberies, purchasing them illegally on the black market, or receiving them from family or friends. These individuals seek to achieve a “high” from prescription medications by taking an excess number of pills orally or by crushing the pills, followed by snorting, smoking, or injecting the new altered formulation.
  • the misuse or abuse of prescription opioid medications is a growing problem, with abuse rates having quadrupled in the decade from 1990 to 2000.
  • T reatments for addiction vary but include efforts to deter psychological and/or physiological dependencies.
  • the symptoms of withdrawal are a major reason for relapse and further prescription drug abuse.
  • Successful, lifelong therapy to stay opioid-free usually involves longterm medication as well as counseling or talk therapy programs. Despite these medications, rates of relapse remain astonishingly high.
  • the addictive substance is an opioid (e.g., fentanyl).
  • the compounds and methods reduce one or more of (a) the craving of an addictive substance, (b) the level of physical dependence of an addictive substance, (c) the tolerance of an addictive substance and/or (d) the rate of relapse.
  • Embodiments include a compound of Formula I:
  • R 1 is OH, OCH3 or OH linked to a C1 -C10 straight or branched alkyl
  • R 2 is a halogen
  • R 3 is NH, NCH3 or N linked to a C1-C10 straight or branched alkyl
  • Embodiments include a compound of Formula II:
  • R 1 is OH, OCH3 or OH linked to a C1 -C10 straight or branched alkyl
  • R 2 is a halogen
  • R 3 is NH, NCH3 or N linked to a C1-C10 straight or branched alkyl, n is 0, 1 , 2, 3 or 4.
  • Embodiments include a compound of D3 (GATC-1021), a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • D3 a compound of D3 (GATC-1021), a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound identified herein, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments also include methods of treating an ailment by administering a therapeutic amount of a compound of Formula I, Formula II or Formula D3.
  • the ailment can be, for example, anxiety, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, depression, Parkinson's disease, stroke, headaches, encephalitis, myasthenia gravis, depression, headaches (e.g., migraines), glaucoma, insomnia, fibromyalgia, a mood disorder (e.g., bipolar), epilepsy, anxiety and/or obsessive-compulsive disorder (OCD).
  • PTSD post-traumatic
  • the compounds described herein are selective HT2A and HTe agonists.
  • the compounds do not have side effects of conventional agonists (e.g., psychedelic effects).
  • the compounds described herein can cross the blood brain barrier.
  • Embodiments include 5-HT2A receptor agonists that do not cause psychedelic side-effects.
  • the compounds are used to treat an ailment or addiction.
  • the compounds promote neuroplasticity.
  • the compounds described herein are useful in improving neuroplasticity.
  • Another embodiment is a method of stimulating neuroplasticity in a subject wherein improving neuroplasticity prevents and/or treats an ailment such as a neurological disorder or addiction.
  • Embodiments include 5-HTe receptor agonists that do not cause psychedelic side-effects.
  • the compounds are used to treat an ailment or addiction.
  • the compounds promote neuroplasticity.
  • Embodiments include compounds that act as both 5-HT2A receptor agonists and 5-HTe receptor agonists.
  • Embodiments also include methods of modulating a G protein-coupled receptor (e.g., 5-HT2A and/or 5-HTe) to treat an ailment and/or an addiction.
  • a G protein-coupled receptor e.g., 5-HT2A and/or 5-HTe
  • the compounds described herein are provided as pro-drugs to improve absorption across the blood brain barrier. Accordingly, aspects include small molecule therapeutics that include an active agent and a pro-drug component. A therapeutic amount of the composition can be administered to treat an ailment or an addiction.
  • the compounds described herein are administered with thiamine.
  • thiamine improves the safety profile of the compound (e.g., by allowing less compound to be administered without decreasing efficacy).
  • the methods described herein include use of a therapeutic amount of thiamine and/or sulbutiamine. In aspects, this can increase the effectiveness and/or efficacy of the therapeutic.
  • the compounds and methods described herein are used to treat addiction.
  • the addiction is to an opioid (e.g., fentanyl, oxycontin, etc.), nicotine, cocaine, an opioid agonist or dependency on stimulants, nicotine, morphine, heroin, other opiates, amphetamines, cocaine, and/or alcohol.
  • opioid e.g., fentanyl, oxycontin, etc.
  • the compounds and methods described herein are used to prevent or reduce the occurrence of an undesired behavior (e.g., tics).
  • the compounds and methods described herein are used to treat an ailment.
  • the ailment can be, for example, anxiety, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, depression, Parkinson's disease, stroke, headaches, encephalitis, myasthenia gravis, depression, headaches (e.g., migraines), glaucoma, insomnia, fibromyalgia, a mood disorder (e.g., bipolar), epilepsy, anxiety and/or obsessive-compulsive disorder (OCD).
  • the ailment is associated with 5-HT2A receptor activity and/or
  • the present specification provides a use of the therapeutic small molecule or the pharmaceutical composition including the same in the preparation of drugs for the prevention or treatment of a neurological disorder or addiction.
  • the therapeutic is administered to a patient as an inhalant.
  • the inhalant is administered via nasal delivery.
  • the compounds described herein can stimulate limbic remodeling and/or neurite outgrowth.
  • Embodiments include methods of treating ailments (e.g., a neurological or brain disorder) by administering a compound described herein (e.g., GATC 1021).
  • a compound described herein e.g., GATC 1021
  • the compound is administered with thiamine or pharmacological equivalent drug, or prodrug (e.g., sulbutiamine and benfotiamine).
  • treatment with sulbutiamine leads to lower absorption of the compounds described herein into the brain.
  • co-administration of the drug with thiamine can produce an improved safety profile.
  • embodiments include methods of improving the bioavailability and/or safety profile of a therapeutic by co-administration with thiamine or a thiamine derivative.
  • Embodiments include methods of treating ailments (e.g., a neurological or brain disorder) by administering a HT2A/HT6 agonist described herein.
  • the compound is administered with thiamine, or pharmacologically equivalent drug or prodrug.
  • the methods described herein lead to a reduction in off target toxicity in HERG or A2A.
  • the methods described herein lead to HT2A/HT6 agonist levels in the brain that are attenuated from agonist administration alone.
  • the methods described herein lead to restoration of the rate of gap junction degradation to homeostatic levels.
  • GATC 1021 (and other compounds) bind to and act as antagonists on the M1 muscarinic receptor. This can result in altered clipping behavior and neurite remodeling leading to limbic remodeling in the brain. The mechanisms indicate that the M1 receptor is involved in addiction.
  • FIG. 1 depicts molecular signaling pathways regulated by the 5-HT2A receptor.
  • FIG. 2 depicts molecular signaling pathways regulated by the 5-HTe receptor.
  • FIG. 3 is a table of 5-HT2A/5-HT6 receptor agonists according to embodiments.
  • references in this specification to "one embodiment/aspect” or “an embodiment/aspect” means that a particular feature, structure, or characteristic described in connection with the embodiment/aspect is included in at least one embodiment/aspect of the disclosure.
  • the use of the phrase “in one embodiment/aspect” or “in another embodiment/aspect” in various places in the specification are not necessarily all referring to the same embodiment/aspect, nor are separate or alternative embodiments/aspects mutually exclusive of other embodiments/aspects.
  • various features are described which may be exhibited by some embodiments/aspects and not by others.
  • various requirements are described which may be requirements for some embodiments/aspects but not other embodiments/aspects.
  • Embodiment and aspect can in certain instances be used interchangeably.
  • neurological disorder broadly refers to a disorder of the nervous system. Neurological disorders can affect the brain as well as the nerves found throughout the human body and the spinal cord.
  • Neurological disorders include, for example, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.
  • ALS Amyotrophic Lateral Sclerosis
  • neurodegenerative disease refers to a disease caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death.
  • Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. They encompass a wide range of conditions that result from progressive damage to cells and nervous system connections that are essential for mobility, coordination, strength, sensation, and cognition.
  • Examples include: Alzheimer's disease and other memory disorders, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, frontotemporal lobar degeneration, frontotemporal dementia; primary progressive aphasia; PNFA: progressive nonfluent aphasia; FTLD-U frontotemporal lobar degeneration with ubiquitin positive inclusions; AD: Alzheimer's Disease; MCI: mild cognitive impairment PD: Parkinson's Disease; DLB: dementia with Lewy bodies and lewy body disease.
  • brain disorder refers to a neurological disorder which affects the brain’s structure and function.
  • Brain disorders can include, for example, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post-traumatic stress disorder (PTSD), suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury and substance use disorder.
  • PTSD post-traumatic stress disorder
  • the term “addiction” can be defined as a biopsychosocial disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences. Addiction affects over 19.7 million people in the United States and presents a high financial and human toll. The total economic cost is greater than that of all types of diabetes and all cancers combined.
  • the term “substance use disorder” or “SUD” can be defined as the persistent use of drugs despite substantial harm and adverse consequences. As an individual becomes increasingly dependent on a drug, discontinued use leads to withdrawal symptoms such as dysphoria. Substance use disorders are characterized by various mental/emotional, physical, and behavioral problems such as chronic guilt, an inability to reduce or stop consuming the substances despite repeated attempts, driving while intoxicated and physiological withdrawal symptoms. The development of dependence has been conceptualized as a neurobehavioral disorder that advances from impulsive drug use to compulsive drug abuse.
  • the term "behavioral addiction” can be defined as a compulsion to engage in a natural reward - which is a behavior that is inherently rewarding (i.e., desirable or appealing) - despite adverse consequences.
  • Precl inical evidence has demonstrated that marked increases in the expression of AFosB through repetitive and excessive exposure to a natural reward induces the same behavioral effects and neuroplasticity as occurs in a drug addiction.
  • BDMA brain disease model of addiction
  • SUDs are chronic, relapsing brain diseases and that relapses are symptoms, and part of the expected course, of the disease.
  • SUDs can have multiple causes, including behavioral, environmental, and biological influences.
  • neuroplasticity also known as neural plasticity, or brain plasticity, refers to the ability of neural networks in the brain to change through growth and reorganization. These changes range from individual neuron pathways making new connections, to systematic adjustments like cortical remapping. Examples of neuroplasticity include circuit and network changes that result from learning a new ability, environmental influences, practice and psychological stress. Neuroplasticity was once thought to manifest only during childhood, but recent research has demonstrated that many aspects of the brain can be altered (i.e., are "plastic") even through adulthood. However, the developing brain exhibits a higher degree of plasticity than the adult brain. Activity-dependent plasticity can have significant implications for healthy development, learning, memory and recovery from brain damage.
  • prevent refers to an approach for preventing the onset or recurrence of a disease or condition, (e.g., addiction, or relapse use or behavior) or preventing the occurrence or recurrence of the symptoms of a disease or condition, or optionally an approach for delaying the onset or recurrence of a disease or condition or delaying the occurrence or recurrence of the symptoms of a disease or condition.
  • prevention refers to an approach for preventing the onset or recurrence of a disease or condition, (e.g., addiction, or relapse use or behavior) or preventing the occurrence or recurrence of the symptoms of a disease or condition, or optionally an approach for delaying the onset or recurrence of a disease or condition or delaying the occurrence or recurrence of the symptoms of a disease or condition.
  • genomics investigates thousands of DNA sequences
  • transcriptomics investigates all or many gene transcripts
  • proteomics investigates large numbers of proteins
  • metabolomics investigates large sets of metabolites.
  • Omic data can include genomic data, transcriptomics, proteomics, epigenomics and metabolomics.
  • Historical data refers to data (e.g. physiological measurements and actions of individuals) recorded and/or stored in a database that can be accessed for analysis and/or comparison.
  • the data can be raw (e.g. sensor data) or processed (e.g. fused data).
  • Historical data can include (a) data compiled from groups/populations of individuals and (b) data compiled from an individual person.
  • data can be recorded from healthy people and people with known ailments.
  • An analysis of the data can indicate variations in physiological measurements that can be correlated with ailments.
  • data from an individual person can be recorded and stored. This can allow the system to identify patterns, variations and/or aberrations in activity for that particular person.
  • additional biomedical information refers to one or more evaluations of an individual, other than using any of the biomarkers described herein, that are associated with health and/or susceptibility to diabetes. Accordingly, “additional biomedical information” includes any of the following: physical descriptors of an individual, the height, weight and/or BMI of an individual, the gender of an individual, the ethnicity of an individual, family history, smoking history, occupational history, etc. Additional biomedical information can be obtained from an individual using routine techniques known in the art, such as from the individual themselves by use of a routine patient questionnaire or health history questionnaire, etc., or from a medical practitioner, etc.
  • formulation refers to the antibodies disclosed herein and excipients combined together which can be administered and has the ability to bind to the corresponding receptors and initiate a signal transduction pathway resulting in the desired activity.
  • the formulation can optionally comprise other agents.
  • administration refers to the introduction of an amount of a predetermined substance into a patient by a certain suitable method.
  • the composition disclosed herein may be administered via any of the common routes, as long as it is able to reach a desired tissue, for example, but is not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal administration.
  • active ingredients of a composition for oral administration should be coated or formulated for protection against degradation in the stomach.
  • active agent refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to.
  • active agent or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed.
  • An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed.
  • An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.
  • pro-drug refers a compound that includes chemical groups which, in vivo, can be converted and/or can be split off from the remainder of the molecule to provide for the active drug, a pharmaceutically acceptable salt thereof, or a biologically active metabolite thereof. Rather than administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted. Pro-drugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract. A pro-drug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This can reduce adverse or unintended effects of a drug.
  • bioavailability refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For example, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. In an embodiment, the bioavailability of an agent is increased by converting it to a prodrug.
  • ECso half maximal effective concentration
  • a “subject” of diagnosis or treatment is, without limitation, a prokaryotic or a eukaryotic cell, a tissue culture, a tissue or an animal, e.g. a mammal, including a human.
  • Non-human animals subject to diagnosis or treatment include, for example, without limitation, a simian, a murine, a canine, a leporid, such as a rabbit, livestock, sport animals, and pets.
  • treating without limitation, to mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder.
  • prognosis refers to the likely outcome or course of a disease and/or the chance of recovery or recurrence. This is in contrast to a “diagnosis” which refers to identifying an ailment or disease, usually from examining a subject. For example, addiction prognosis refers to whether the addiction will respond to treatment or mitigation efforts and/or the likelihood that it will progress.
  • the term “health evaluation” or “health assessment” refers to a plan of care that identifies the specific needs of a person and how those needs will be addressed by the healthcare system or healthcare provider. Conventionally, a health assessment follows an evaluation of a subject’s health status by performing a physical exam after taking a health history.
  • biomarker refers generally to a DNA, RNA, protein, carbohydrate, or glycolipid-based molecular marker, the expression or presence of which in a sample can be detected by standard methods (or methods disclosed herein) and is predictive or prognostic of the effective responsiveness or sensitivity of a mammalians subject with an ailment. Biomarkers may be present in a test sample but absent in a control sample, absent in a test sample but present in a control sample, or the amount or of biomarker can differ between a test sample and a control sample.
  • protein biomarkers can be present in such a sample, but not in a control sample, or certain biomarkers are seropositive in the sample, but seronegative in a control sample. Also, expression of such a biomarker may be determined to be higher than that observed from a control sample.
  • the terms "marker” and “biomarker” are used herein interchangeably.
  • the term “physiological event” refers to a response or reaction of the body to a stimulus. Most are automatic/instinctive physiological responses.
  • the healthy state of the body depends upon the integrity of various organ systems.
  • the organ systems in the body function in a particular manner constantly.
  • the mechanisms, by which the organ systems of the body function can be referred to as “physiological mechanisms.”
  • Physiological mechanisms explain any health-related events or outcomes. Physiological mechanisms can be altered voluntarily. For example, exercise causes alteration in the cardiac physiology of resting state.
  • the term “stimulant” refers to a substance that increases activity of the central nervous system and/or the body. Stimulants are widely used as prescription medicines as well as without a prescription (either legally or illicitly) as performanceenhancing or recreational drugs. Most stimulants exert their activating effects by enhancing catecholamine neurotransmission. Common stimulants include, amphetamine, caffeine, ephedrine, MDMA, MDPV, mephedrone, methamphetamine, methylphenidate, cocaine, phenylpropanolamine, propylhexedrine, pseudoephedrine, Catha edulis (Khat) and modafinil.
  • 5-HT2A receptor refers to a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR).
  • GPCR G protein-coupled receptor
  • the 5-HT2A receptor is a cell surface receptor but has several intracellular locations.
  • 5-HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex.
  • 5-HT2A receptor agonist refers to a substance that initiates a physiological response when combined with the 5-HT2A receptor. Activation of the 5- HT2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched. Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity.
  • 5-HTe receptor agonist refers to a substance that initiates a physiological response when combined with the 5-HTe receptor.
  • sulbutiamine refers to a synthetic derivative of thiamine (vitamin B1). It can be used to treat thiamine deficiency. Because thiamine deficiency causes problems with memory and other cognitive functions, thiamine and analogs like sulbutiamine have been studied in clinical trials for age-associated cognitive decline. Sulbutiamine has been explored in clinical trials as a potential treatment for chronic fatigue syndrome. It is sold commercially under the brand names ArcalionTM and EnerionTM.
  • thiamine is administered in a prodrug form.
  • Recent efforts have focused on developing thiamine derivatives with better bioavailability. These efforts led to the discovery of allicin (diallyl thiosulfinate), sulbutiamine, fursultiamine (thiamine tetrahydrofurfuryl disulfide) and benfotiamine. These compounds are hydrophobic, easily pass from the intestines to the bloodstream, and are reduced to thiamine by cysteine or glutathione.
  • TrkB also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). The TrkB receptor is part of the large family of receptor tyrosine kinases.
  • blood-brain barrier refers to a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system where neurons reside.
  • the blood-brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function.
  • omics refers to comprehensive approaches for analysis of complete genetic or molecular profiles of humans and other organisms. Since the process of mapping and sequencing the human genome began, new technologies have made it possible to obtain a huge number of molecular measurements within a tissue or cell. These technologies can be applied to a biological system of interest to obtain a snapshot of the underlying biology at a resolution that has never before been possible. Broadly speaking, the scientific fields associated with measuring such biological molecules in a high-throughput way are called “omics.”
  • combination therapy refers to a method of treating a disease or disorder, wherein two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents.
  • the compounds of the invention can be used in combination with other pharmaceutically active compounds.
  • the compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy.
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • a compound of a given Formula (e.g. , the “compound of Formula D3”) is intended to encompass the compounds of the disclosure, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, hydrates, polymorphs, and prodrugs of such compounds. Additionally, the compounds of the disclosure may possess one or more asymmetric centers and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of a given Formula depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound by conventional means.
  • composition is intended to include the combination of an active agent (i.e., a prodrug therapeutic) with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.
  • the term “isomer” refers to different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers. Similarly, “stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1 :1 mixture of a pair of enantiomers is a “racemic” mixture.
  • the term “(+)” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • salt refers to an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2- acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC— (CH2)n— COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, s
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in an appropriate solvent.
  • composition is intended to include the combination of an active agent with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.
  • neural outgrowth refers to a process in which developing neurons create new projections as they grow in response to guidance cues. It is a fundamental process in neuronal differentiation and is important in the study of normal development and regeneration. It is also used to study how neurite outgrowth is inhibited or stimulated in disorders such as Alzheimer's disease and Parkinson's disease.
  • formulation(s) means a combination of at least one active ingredient with one or more other ingredients, also commonly referred to as excipients, which may be independently active or inactive.
  • formulation may or may not refer to a pharmaceutically acceptable composition for administration to humans or animals and may include compositions that are useful intermediates for storage or research purposes.
  • the patients and subjects of the invention method are, in addition to humans, veterinary subjects, formulations suitable for these subjects are also appropriate.
  • Such subjects include livestock and pets as well as sports animals such as horses, greyhounds, and the like.
  • Embodiments of the invention relate to the fields of addiction and mental health. Particular embodiments include compounds and methods for treating mental health ailments and/or addictions. Specifically, aspects of the invention include novel compounds that are selective HT2A and HTe receptor agonists. The compounds were validated in silico and screened for targeting, ADME (i.e., absorption, distribution, metabolism and excretion) and toxicity.
  • ADME i.e., absorption, distribution, metabolism and excretion
  • the 5-HT2A receptor is a widely expressed Gq-coupled protein receptor (GCPR) that triggers a range of intracellular pathways.
  • GCPR Central nervous system
  • CNS Central nervous system
  • 5-HT2A is implicated in the pathology of several cognitive and learning disorders including schizophrenia, obsessive-compulsive disorder (OCD) and depression.
  • OCD obsessive-compulsive disorder
  • the highest density of 5- HT2A receptors is found in levels 1 , 4, and 5a of the cortex, with medial expression levels in the olfactory bulb, brainstem, and dorsal horn of the spinal cord.
  • 5-HT2A is also expressed by a range of CNS cells, including pyramidal neurons and glia, and has several intracellular locations.
  • FIG. 1 depicts 5-HT2A receptor signaling pathways in mesangial kidney cells.
  • the 5-HT2AR is coupled to PLC and PLD via Gaq protein and plays a role in the control of cell proliferation and fibrosis.
  • the 5-HTe receptor is a G-protein-linked receptor, and is expressed primarily in the striatum, olfactory tubercle, frontal and entorhinal cortex, nucleus accumbens, hippocampus and molecular layer of the cerebellum.
  • Pharmacological blockade of 5-HTe receptor had been shown to produce promnesic or antiamnesic effects (or both) in a number of memory tasks, and emergent evidence indicates that its agonists also seem facilitate memory in diverse memory tasks; the reasons for apparent paradox of promnesic and/or anti amnesic effects of 5-HTe receptor agonists and antagonists are unclear.
  • the development of potent and selective 5- HTe receptor antagonists has been crucial in the clarification of the role of 5-HTe receptor role on memory; in addition, the findings that 5-HTe receptor agonists can improve memory are providing new insights.
  • FIG. 2 depicts 5-HTe receptor signaling pathways.
  • the 5-HTe receptor is positively coupled to AC/cAMP pathway via Gas protein. Its stimulation inhibits K+ channel (GIRK) conductance in neurons and activates kinases via a direct interaction of the receptor C-terminus with interacting proteins, which produces ERK phosphorylation or Jun translocation to the nucleus.
  • GIRK K+ channel
  • Applicants have discovered that agonists of 5-HT2A receptor and 5-HTe receptor can be used therapeutically to treat mental health ailments and addiction. Accordingly, embodiments include selective HT2A and HTe agonists that can be used therapeutically. In aspects, the compounds are capable of crossing the blood brain barrier to reach a target tissue.
  • Embodiments include a compound of Formula I:
  • R 1 is OH, OCH3 or OH linked to a C1 -C10 straight or branched alkyl
  • R 2 is a halogen
  • R 3 is NH, NCH3 or N linked to a C1-C10 straight or branched alkyl
  • Embodiments include a compound of Formula II:
  • R 1 is OH, OCHs or OH linked to a C1 -C10 straight or branched alkyl
  • R 2 is a halogen
  • R 3 is NH, NCH3 or N linked to a C1-C10 straight or branched alkyl, n is 0, 1 , 2, 3 or 4.
  • Embodiments include a compound of D3 (GATC-1021), a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • D3 a compound of D3 (GATC-1021), a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1002, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1005, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • GATC-1005 a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1007, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • GATC-1007 a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1010, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1011 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1013, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1015, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1016, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • GATC-1016 a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1020, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Embodiments include a compound of GATC-1021 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • the compounds may be provided and/or administered as a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.
  • Methods for treating, preventing or ameliorating a disease, disorder, a condition, an addiction or a symptom thereof or a condition related thereto are provided herein.
  • Preferred, but non-limiting embodiments are directed to methods for treating, preventing, inhibiting or ameliorating a disease, disorder, a condition, an addiction or a symptom described below.
  • a subject is provided with an effective amount of a compound as described herein (see FIG. 3).
  • an “effective amount” or a “therapeutically effective amount” of a substance is that amount sufficient to affect a desired biological or psychological effect, such as beneficial results, including clinical results.
  • an effective amount of a compound D3 is that amount sufficient to cause the subject to reduce or discontinue use of an addictive agent (e.g., fentanyl).
  • an effective amount of a compound of D3 is an amount sufficient to cause the subject to reduce or discontinue the addictive behavior.
  • compositions described herein can be mixed with a pharmaceutical acceptable carrier, adjuvant and/or excipient, according to conventional pharmaceutical compounding techniques.
  • Pharmaceutically acceptable carriers that can be used in the present compositions encompass any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • the compositions can additionally contain solid pharmaceutical excipients such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, etc.
  • Liquid and semisolid excipients can be, for example, glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the compositions also can include stabilizers and preservatives.
  • the invention encompasses the use, where applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds of the invention, as well as mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds of the invention, and mixtures thereof, are within the scope of the invention.
  • the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other.
  • the compounds can be provided as a substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).
  • the compounds described herein can be asymmetric (e.g. , having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the invention unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • prototropic tautomers include, but are not limited to, ketoneenol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system including, but not limited to, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 , 2 ,4-triazole, 1 H- and 2H-isoindole, and 1 H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds also include hydrates and solvates, as well as anhydrous and non-solvated forms. Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
  • the compounds, or salts thereof are substantially isolated.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • One or more of the compounds described herein can be administered by any method known in the art, including, for example, intranasal, oral, transdermal, ocular, intraperitoneal, inhalation, intravenous, ICV, intracisternal injection or infusion, subcutaneous, implant, vaginal, sublingual, urethral (e.g., urethral suppository), subcutaneous, intramuscular, intravenous, rectal, sub-lingual, mucosal, ophthalmic, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial and lymphatic administration.
  • a topical formulation can be in the form of gel, ointment, cream, aerosol, etc.
  • An intranasal formulation can be delivered as a spray or in a drop.
  • a prodrug formulation can be administered via a transdermal patch or iontophoresis.
  • a formulation for inhalation can be delivered using a nebulizer or similar device.
  • Compositions can also take the form of tablets, pills, capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols or any other appropriate compositions.
  • certain embodiments are directed to a sustained release drug delivery platform that releases a therapeutic compound or compounds disclosed and made as a formulation described herein over a period of, without limitation, about 3 days after administration, about 7 days after administration, about 10 days after administration, about 15 days after administration, about 20 days after administration, about 25 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration.
  • a sustained release drug delivery platform releases a therapeutic compound or compounds disclosed herein with substantially first order release kinetics over a period of, without limitation, at least 3 days after administration, at least 7 days after administration, at least 10 days after administration, at least 15 days after administration, at least 20 days after administration, at least 25 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.
  • the therapeutic agents in the pharmaceutical compositions may be formulated in a "therapeutically effective amount” or a “prophylactically effective amount".
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the recombinant vector may vary depending on the condition to be treated, the severity and course of the condition, the mode of administration, whether the antibody or agent is administered for preventive or therapeutic purposes, the bioavailability of the particular agent(s), the ability of the agent to elicit a desired response in the individual, previous therapy, the age, weight and sex of the patient, the patient's clinical history and response to the antibody, the type of the agent used, discretion of the attending physician, etc.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the recombinant vector is outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.
  • a therapeutically effective amount or prophylactically effective amount of the agent will be administered in a range from about 1 ng/kg body weight/day to about 100 mg/kg body weight/day whether by one or more administrations.
  • each agent is administered in the range of from about 1 ng/kg body weight/day to about 10 mg/kg body weight/day, about 1 ng/kg body weight/day to about 1 mg/kg body weight/day, about 1 ng/kg body weight/day to about 100 g/kg body weight/day, about 1 ng/kg body weight/day to about 10 g/kg body weight/day, about 1 ng/kg body weight/day to about 1 g/kg body weight/day, about 1 ng/kg body weight/day to about 100 ng/kg body weight/day, about 1 ng/kg body weight/day to about 10 ng/kg body weight/day, about 10 ng/kg body weight/day to about 100 mg/kg body weight/day, about 10 ng/kg body weight/day, about 10 ng/kg body
  • each agent is administered in the range of about 10 ng to about 100 ng per individual administration, about 10 ng to about 1 g per individual administration, about 10 ng to about 10 g per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1 mg per individual administration, about 10 ng to about 10 mg per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1000 mg per individual administration, about 10 ng to about 10,000 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 5 mg per individual administration
  • each agent is administered in the range of about 10 ng to about 100 ng per injection, about 10 ng to about 1 g per injection, about 10 ng to about 10 g per injection, about 10 ng to about 100 mg per injection, about 10 ng to about 1 mg per injection, about 10 ng to about 10 mg per injection, about 10 ng to about 100 mg per injection, about 10 ng to about 1000 mg per injection, about 10 ng to about 10,000 mg per injection, about 100 ng to about 1 mg per injection, about 100 ng to about 10 mg per injection, about 100 ng to about 100 mg per injection, about 100 ng to about 1 mg per injection, about 100 ng to about 10 mg per injection, about 100 ng to about 100 mg per injection, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 5 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 100
  • the agent may be injected hourly, bi-hourly , tri-hourly , every 90 minutes, every two hours, every three hours, every four hours, twice daily, three times daily, four times daily, five times daily, six times daily, seven times daily, eight times daily, every 2, 3, 4, 5, 6 or 7 days, or every 1 , 2, 3 or 4 weeks.
  • the amount of the agent may be administered at a dose of about 0.0006 mg/day, 0.001 mg/day, 0.003 mg/day, 0.006 mg/day, 0.01 mg/day, 0.03 mg/day, 0.06 mg/day, 0.1 mg/day, 0.3 mg/day, 0.6 mg/day, 1 mg/day, 3 mg/day, 6 mg/day, 10 mg/day, 30 mg/day, 60 mg/day, 100 mg/day, 300 mg/day, 600 mg/day, 1000 mg/day, 2000 mg/day, 5000 mg/day or 10,000 mg/day.
  • the dosage will be dependent on the condition, size, age and condition of the patient.
  • a pharmaceutical composition disclosed herein reduces the prevalence or likelihood of relapse by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • a pharmaceutical composition disclosed herein reduces the prevalence or likelihood of relapse from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • a pharmaceutical composition disclosed herein is in an amount sufficient to allow customary administration to an individual.
  • a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a pharmaceutical composition.
  • a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 ,000 mg, at least 1 , 100 mg, at least 1 ,200 mg, at least 1 ,300 mg, at least 1 ,400 mg, or at least 1 ,500 mg of a pharmaceutical composition.
  • a pharmaceutical composition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg.
  • a pharmaceutical composition disclosed herein may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1 ,000 mg, about 10 mg to about 1 ,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1 ,000 mg, about 50 mg to about 1 ,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1 ,000 mg, about 100 mg to about 1 ,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1 ,000 mg, about 200 mg to about 1 ,500 mg, about 5 mg to about 1 ,500 mg, about 5 mg to about 1 ,000 mg, or about 5 mg to about 250 mg.
  • a pharmaceutical composition disclosed herein can also include an effective amount of thiamine and/or sulbutiamine.
  • a pharmaceutical composition disclosed herein can include, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of thiamine and/or sulbutiamine in a pharmaceutical composition.
  • a pharmaceutical composition disclosed herein can include, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 ,000 mg, at least 1 , 100 mg, at least 1 ,200 mg, at least 1 ,300 mg, at least 1 ,400 mg, or at least 1 ,500 mg of thiamine and/or sulbutiamine.
  • a pharmaceutical composition disclosed herein can include thiamine and/or sulbutiamine in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg.
  • a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or other diluent in an amount sufficient to dissolve a pharmaceutical composition disclosed herein.
  • a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or a diluent in an amount of, e.g., less than about 90% (v/v), less than about 80% (v/v), less than about 70% (v/v), less than about 65% (v/v), less than about 60% (v/v), less than about 55% (v/v), less than about 50% (v/v), less than about 45% (v/v), less than about 40% (v/v), less than about 35% (v/v), less than about 30% (v/v), less than about 25% (v/v), less than about 20% (v/v), less than about 15% (v/v), less than about 10% (v/v), less than about 5% (v/v), or less than about 1 % (v/v).
  • a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or other diluent in an amount in a range of, e.g., about 1% (v/v) to 90% (v/v), about 1 % (v/v) to 70% (v/v), about 1% (v/v) to 60% (v/v), about
  • the final concentration of a pharmaceutical composition disclosed herein may be of any concentration desired.
  • the final concentration of a pharmaceutical composition disclosed herein may be a therapeutically effective amount.
  • the final concentration of a pharmaceutical composition disclosed herein may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1 ,000 mg/mL, or at least 1 ,200 mg/mL.
  • the concentration of a pharmaceutical composition disclosed herein in the solution may be, e.g., at most 1 ,000 mg/mL, at most 1 ,100 mg/mL, at most 1 ,200 mg/mL, at most 1 ,300 mg/mL, at most 1 ,400 mg/mL, at most 1 ,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL.
  • the final concentration of a pharmaceutical composition disclosed herein may be in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1 ,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1 ,000 mg/mL to about 2,000 mg/mL, about 750 mg/
  • the final concentration of thiamine and/or sulbutiamine in a composition disclosed herein can be of any concentration desired.
  • the final concentration is a therapeutically effective amount.
  • the final concentration of a thiamine and/or sulbutiamine is e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1 ,000 mg/mL, or at least 1 ,200 mg/mL.
  • the concentration can be, e.g., at most 1 ,000 mg/mL, at most 1 ,100 mg/mL, at most 1 ,200 mg/mL, at most 1 ,300 mg/mL, at most 1 ,400 mg/mL, at most 1 ,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL.
  • the final concentration of a pharmaceutical composition disclosed herein may be in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1 ,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1 ,000 mg/mL to about 2,000 mg/mL, about 750 mg/
  • the term “treating,” refers to reducing or eliminating in an individual a symptom of addiction; or delaying or preventing relapse in an individual.
  • the term “treating” can mean reducing a symptom (e.g., craving and/or physiological dependence) by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%.
  • a pharmaceutical composition disclosed herein reduces the severity of a symptom of a disorder associated with addiction.
  • a pharmaceutical composition disclosed herein reduces the severity of a symptom of a disorder associated with addiction by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • a pharmaceutical composition disclosed herein reduces the severity of a symptom of a disorder associated with addiction by, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with addiction by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%.
  • a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with addiction by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%.
  • a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with cancer by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.
  • a therapeutically effective amount of a pharmaceutical composition disclosed herein generally is in the range of about 0.001 mg/kg/day to about 100 mg/kg/day.
  • an effective amount of a pharmaceutical composition disclosed herein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day.
  • an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day.
  • an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day.
  • an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.
  • Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art.
  • treatment of a cancer may comprise a one-time administration of an effective dose of a pharmaceutical composition disclosed herein.
  • treatment of a cancer may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly.
  • the timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms.
  • an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy.
  • a person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.
  • the prodrugs can cross the blood-brain barrier. In some embodiments, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of the prodrug crosses the blood brain barrier.
  • the prodrugs increase the half-life of a small molecule active agent that is administered to a subject.
  • the half-life is increased by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% compared to a non-conjugated active agent.
  • compositions As described above, if desired, other therapeutic agents can be employed in conjunction with those provided in the above-described compositions.
  • the amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.
  • a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration.
  • One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.
  • Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.
  • compositions can be combined with other therapeutic agents in conjunction with those provided in the above-described compositions.
  • amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.
  • a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration.
  • One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.
  • Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.
  • Compound D3 was identified as having an appropriate Al targeting profile (i.e., an agonist of both HT2A and HTe).
  • Compound D3 was prepared as a salt, and formulated as a DMSO, Tween 80, PBS mixture and dosed IP (via intraperitoneal injection) to rats at 25, 50 or 70 mg/Kg daily.
  • One group received only D3; a second group received D3 and sulbutiamine; a control group received only sulbutiamine.
  • Compound D3 along with the compounds and analogs disclosed herein can be prepared according to established methodology in the art of organic synthesis. General methods of synthesizing the compound can be found in, e.g., Stuart Warren and Paul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach, second Edition, Wiley, 2010.
  • the compounds also include pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof, solvates thereof and polymorphic crystals thereof.
  • the compounds can be administered as pharmaceutical compositions.
  • Rats are subject to rodent intravenous drug self- administration paradigm. Specifically, rats are implanted with chronic, indwelling catheters in the jugular vein. The catheter exits the rat on the dorsum, where it is connected to a tether-and-tubing system that is attached to a drug-loaded syringe. Responding on the active lever leads to infusions of the drug.
  • rats are exposed to an opioid drug.
  • Two populations of rats are exposed: a first population is then treated with compound D3 + sulbutiamine and a second population (i.e. , control) is left untreated or injected with sulbutiamine alone.
  • the treated population of rats is compared with the control group.
  • the ratio of active to inactive lever press responses is compared between the populations.
  • the results demonstrate lower rates of level press responses in rats treated with compound D3 + sulbutiamine.
  • the results indicate that compound D3 (or analog) prevents addiction and/or aid in recovery from addiction.
  • a patient suffers from addiction to fentanyl.
  • the patient has used the drug daily and displays a physical dependence to the drug.
  • Conventional methods of treating her addiction have been ineffective.
  • a health care provider suggests use of the compound of D3 along with sulbutiamine.
  • the formulation is provided in solution for injection.
  • the patient is administered a single dose of the formulation. She undergoes bi-weekly addiction counseling and returns to the clinic for weekly injections.
  • Embodiments also include a compound for formula GATC-102, GATC-105, GATC-107, GATC-110, GATC-111 , GATC-113, GATC-115, GATC-116, GATC- 120, GATC-121 , GATC-001 , GATC-002, GATC-003, GATC-004, GATC-005, GATC-007, GATC-008, GATC-009, GATC-012, GATC-018, GATC-020, GATC- 021 , GATC-022, GATC-022-P1 , GATC-022-P2, GATC-024, GATC-026, GATC-033, GATC-042, GATC-046, GATC-047, GATC-049, GATC-050, GATC-051 , GATC-05

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des modes de réalisation de la présente invention comprennent de petites molécules thérapeutiques destinées à être utilisées dans le traitement de l'addiction et de troubles neurologiques. Les petites molécules thérapeutiques peuvent agir en tant qu'agonistes du récepteur 5-HT2A et/ou agonistes du récepteur 5-HT6. Contrairement aux agonistes classiques, les composés de l'invention ne provoquent pas d'effets secondaires psychédéliques. Dans certains aspects, les composés sont utilisés pour traiter une affection ou une addiction. Dans certains aspects, les composés favorisent la neuroplasticité.
PCT/US2024/042162 2023-08-13 2024-08-13 Composés et méthodes de traitement de la dépendance Pending WO2025038666A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363532417P 2023-08-13 2023-08-13
US63/532,417 2023-08-13

Publications (2)

Publication Number Publication Date
WO2025038666A2 true WO2025038666A2 (fr) 2025-02-20
WO2025038666A3 WO2025038666A3 (fr) 2025-03-27

Family

ID=94632657

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/042162 Pending WO2025038666A2 (fr) 2023-08-13 2024-08-13 Composés et méthodes de traitement de la dépendance

Country Status (1)

Country Link
WO (1) WO2025038666A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9113802D0 (en) * 1991-06-26 1991-08-14 Smithkline Beecham Plc Medicaments
EP1771176A2 (fr) * 2004-06-30 2007-04-11 Smithkline Beecham Corporation Methodes et compositions
MX2012010820A (es) * 2010-03-22 2012-10-10 Actelion Pharmaceuticals Ltd Derivados de 3-(heteroaril-amino)-1, 2, 3, 4-tetrahidro-9h-carbazo l y sus uso como moduladores del receptor de prostaglandina d2.
WO2020176599A1 (fr) * 2019-02-27 2020-09-03 The Regents Of The University Of California Azépino-indoles et autres hétérocycles pour traiter des troubles du cerveau

Also Published As

Publication number Publication date
WO2025038666A3 (fr) 2025-03-27

Similar Documents

Publication Publication Date Title
Burns et al. DARK classics in chemical neuroscience: fentanyl
Kreek et al. Pharmacotherapy of addictions
CN105473135B (zh) 用于治疗精神症状的d-美沙酮
Ward et al. Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder
Aguero et al. Discovery of a novel non-narcotic analgesic derived from the CL-20 explosive: synthesis, pharmacology, and target identification of thiowurtzine, a potent inhibitor of the opioid receptors and the ion channels
Zhang et al. Drug development in channelopathies: Allosteric modulation of ligand-gated and voltage-gated ion channels
US20250129025A1 (en) Methods of treating ptsd and neurological disorders
US20240350510A1 (en) Methods and compositions for reducing tolerance to opioid analgesics using ibogaine and derivatives thereof
Feng et al. Machine-learning analysis of opioid use disorder informed by MOR, DOR, KOR, NOR and ZOR-based interactome networks
Sabino et al. Sigma receptors and substance use disorders
Harris et al. Novel GluN2B-selective NMDA receptor negative allosteric modulator possesses intrinsic analgesic properties and enhances analgesia of morphine in a rodent tail flick pain model
Duron et al. Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment
WO2025038666A2 (fr) Composés et méthodes de traitement de la dépendance
WO2013173730A2 (fr) Nouvelles applications thérapeutiques de peptides du récepteur opioïde mu
Ogura et al. Intravenous opioid agonists and antagonists
Malinky et al. DARK classics in chemical neuroscience: Loperamide
CN111050800B (zh) 血清素3受体激动剂对疼痛的治疗
Teklezgi et al. Mass spectrometric imaging of the brain demonstrates the regional displacement of 6-monoacetylmorphine by naloxone
US20190336486A1 (en) Methods for treating cancer and metabolic syndrome
AU2015363757B2 (en) Diarylmethylidene piperidine derivatives and their use as delta opioid receptor agonists
Martin et al. Pharmacology of drugs of abuse
Rabbani et al. 1. Pharmacological therapeutics and implications of opioid administration in veterinary practices: A current perspective
Baldo et al. Opioid Analgesic Drugs
Burkhardt The Identification of New Directions for the Research of ADHD
Zare et al. Wake-Promoting agents; insights into clinical use and molecular perspectives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24854830

Country of ref document: EP

Kind code of ref document: A2