Compounds and methods for treating neuroinflammation and neuropathologies

Abstract

The disclosure provides, inter alia, methods of treating neuroinflammation, particularly neuroinflammation due to increase in brain IL-1B, methods of stimulating a vagus nerve, and methods of treating a neuropathology caused by neuroinflammation related to increases in IL-1B by administering to a patient a compound that is a positive allosteric modulator of GABA-A receptors.

Description

PATENTDocket No. 056769-503001 WOCOMPOUNDS AND METHODS FOR TREATING NEUROINFLAMMATION AND NEUROPATHOLOGIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to US Application No. 63 / 730,585 filed December 11, 2024, the disclosure of which is incorporated by reference herein for all purposes.BACKGROUND

[0002] The proper function of the immune system [1. 2] is necessary for survival, and malfunction of the immune system is a major contributor to morbidity and mortality in humans [3], The function of the immune system is most times described as an inflammatory response” and under normal conditions, the inflammatory response protects the host from bacteria, viruses, toxins, and infections by ridding the host of the pathogen and promoting tissue repair and recovery [2], The beneficial components of the inflammatory response have been referred to as the “acute inflammatory response,” [4] but when the inflammatory response loses its selflimiting control, it transforms from beneficial to destructive, and predisposes to debilitating diseases of brain, cardiovascular system, liver, kidney, and lung, and to functional decline in aging [4], The inflammatory condition that has lost its self-limiting nature is referred to as “chronic inflammation” [4], Additionally, in older individuals a state of chronic inflammation can arise from a process called “cellular senescence.” This process is characterized by arrest of cell proliferation and development of a secretory' phenotype. The secretory phenoty pe features an increased release of inflammatory- cytokines, chemokines, and other pro-inflammatory agents from the senescent cells [3], This secretory phenotype involves many cell types (e.g., microglia, astrocytes, myocytes) and sustains a chronic inflammatory condition in brain and periphery.

[0003] The brain has, in the past, been considered as an immune privileged organ, protected from systemic infections and reactive peripheral immune elements by the blood / brain barrier (BBB). This view has been significantly modified. In the current thinking, the BBB is not as impermeable as previously thought and. although retarded by the BBB. antigenic substances and activated immune cells can enter the central nervous system (CNS) environment [5], The CNS is also served by its own immune system composed primarily of microglia, astrocytes, macrophages, and T and B cells [6], The brain immune system can respond to antigenic substances entering from the periphery’, and to the peripheral immune cells (monocytes, macrophages, etc.) and their signaling molecules (cytokines, chemokines, etc.), by mounting itsPATENT own immune response, which can be acute or chronic [6], The CNS immune system can also respond to damage or metabolic malfunction within the CNS without the interposition of the peripheral elements. This can be clearly seen with cases of traumatic brain injury or neural degeneration [7], But just as in the periphery, an acute inflammatory response in the CNS can be beneficial while chronic inflammation can promote neurodegeneration and is instrumental in anatomical and functional damage to brain and spinal cord (CNS). The term neuroinflammation, as we use it, is applied to the chronic inflammatory response in the CNS and the events involved in this chronic inflammation are those mediated by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers produced primarily by the microglia and astrocytes endogenous to the CNS [1-3],

[0004] The transition of microglia and astrocytes from a resting, surveillance phenoty pe to an activated state, releasing pro-inflammatory and neurodegenerative cytokines (e.g., IL-6, IL-1 P) and other agents, e.g., tumor necrosis factor a (TNFa) that damage tissue can be monitored in a state of chronic inflammation by changes in the immune cell morphology7[8], For instance, microglia retract their processes and transform themselves into a compact “amoeboid” morphology when they are fully activated [8-10], Thus, immunological activation of microglia and astrocytes can be monitored both by the release of high levels of neuroinflammatory cytokines (e.g., IL-1 ) and TNFa, and by the morphological characteristics of the brain immune cells [3, 9, 11], It is these characteristics that have linked the activated immune system and chronic inflammation to neurodegeneration characteristic of the pathology seen in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease, traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), schizophrenia, depression, and epilepsy ([3, 12, 13] and Table 1), as well as to changes in neuroanatomy and CNS signaling involved in development of substance use disorders (SUDs)

[0014] ,

[0005] Targeting chronic neuroinflammation as a means of treatment of neurodegenerative disease has become popular. A good example of this approach is the development of a vector which delivers a dominant negative variant of soluble TNFa (DN-TNF) to the brain. DN-TNF can selectively inactivate soluble TNFa

[0015] without suppressing the other components of innate immunity7and is currently in clinical trials for treatment of Alzheimer’s disease. INmune DN- TNF is also being readied for Phase 2 trials for treatment of depression resistant to other therapies

[0015] , Another drug targeting the immune system, NP001 (by Neuvivo). is being tested in the clinic for treatment of ALS. This medication targets inappropriately activated macrophages and microglia to convert them to the resting state focused on the wound / damagePATENT healing phenoty pe

[0016] , Problems do exist with the current and past approaches using drug molecules in attempts to treat neuroinflammation and neurodegenerative diseases. These problems are primarily in the realm of targeting the appropriate immune or other cells, or particular cytokines (e.g., IL-1 P) that promote chronic inflammation in the CNS, without suppressing the innate immune response throughout the body, or suppressing the beneficial (acute) actions of the immune systems of brain. As already mentioned, a cytokine that is a notable contributor to neuroinflammation is a member of the Interleukin 1 (IL- 1 ) family. IL- 1 is produced in both neurons and glial cells in the CNS

[0017] and is one of the IL-1 family members (IL-ip, IL-18, IL-33) that is translated as a pro-peptide and requires processing by inflammasome caspase-mediated hydrolysis to produce the active form of the cytokine

[0018] , Although the general path for processing of the IL-1 family cytokines is similar, the caspases involved and triggering of active cytokine production is unique for these members of the IL- 1 family

[0018] , This is well exemplified by the example that IL- 18 is constitutively expressed while the transcription, translation, processing, and release of IL-ip is strictly “on demand'’

[0019] , Thus, when discussing neuroinflammation and particular cytokines, the stimulus, cell type releasing the cytokine, and the mechanism intervening between the stimulus and the synthesis and release of the cytokine are all of importance.

[0006] Another approach to reducing chronic neuroinflammation and providing benefit in neurodegenerative disorders is electrical stimulation of the vagus nerve (10th cranial nerve) [20, 21], Of the various branches of the vagus nerve, the afferent neurons of the vagus nerve innervating the gut have recently received substantial attention in this regard [22-24], This attention is a result of studies indicating that the microbiota of the gut can communicate with brain through activation of the intestinal vagal afferents traveling to the nucleus tractus solitarius (NTS) in the brainstem

[0025] , The terminals of the afferent neurons of the vagus nerve in the intestine express receptors for endogenous neurotransmitters (e g., serotonin, acetylcholine, etc.), hormones (CCK, GLP-1, etc.), antigens (pattern recognition receptors (PRRs), e.g., TL4, which recognize pathogen-associated molecular patterns [PAMPs]), and nutrients (glucose, amino acids)

[0024] , Other chemical substances, e.g., Sertraline, an antidepressant medication, can also activate the firing of the afferent vagal neurons innervating the gut

[0026] , but the mechanism by which this event takes place has not been investigated. Indirect pathways are also available for vagal stimulation by chemical substances. For instance, nutrients can activate release of hormones from enteroendocrine cells which in turn activate the vagus and signal the brain to generate the feeling of hunger or satiation [27-29], It should be noted that enteroendocrine cells (e.g., those that are responsive to lipids in the diet and release CCK) are also modulated byPATENTGABA via the GABA-A receptors expressed on their basal membranes

[0030] , The enteric nervous system, located in the intestine, also communicates with brain through the vagus, through chemical synapses, and informs the brain of the mechanical actions of the gut

[0029] ,

[0007] In a recent review, Kelly et al.

[0031] summarized the available data on how signals generated by the vagus nerve can modulate the inflammatory actions of macrophages and other cells of the immune system. In this review, Kelly et al.

[0031] focused on the historical evidence that emphasizes the fact that stimulation of the vagus nene can form a therapeutic platform targeting chronic inflammatory diseases. A more recent review also emphasizes the findings that vagus nerve stimulation can modulate the neuroimmune system

[0021] , Although much evidence is accumulating that electrical stimulation of the afferent arm of the vagus nerve leading to brain is a means of activating an anti-inflammatory response, no therapeutic agents (drugs) have been developed to generate such communication between the afferent vagus and brain.

[0008] It has been demonstrated that peripheral administration of the antigenic principal of the gram-negative bacterial cell wall, an endotoxin lipopolysaccharide referred to as LPS, can produce neuroinflammation by activating microglia and astrocytes in the CNS

[0032] , To experimentally produce such inflammation in the CNS, LPS can be administered either by intraperitoneal injection into the abdomen or intragastrically

[0025] , The injected or ingested antigen (LPS), or other neuroinflammatory substance, can reach the brain via the circulation and affect brain function. However, the vagus nerve can also respond to the presence of bacterial products or the bacteria per se in the periphery and rapidly mount an anti-inflammatory response throughout the body

[0022] , The vagus innervates most peripheral organs and is a major component of the autonomic (parasympathetic) nervous system

[0033] involved with maintaining homeostasis throughout the body. The afferent fibers of the vagus nerve carry sensory information from the milieu of the peripheral organs to the brain, and the efferent fibers carry response information back to the organ from which the signal arose, or to other organs, to mount the proper response. When vagal afferent (sensory) neurons are activated by cytokines and bacterial antigens in the periphery they can relay information via the NTS, located in the brainstem, to the hypothalamus, to activate the hypothalamic-pituitary-adrenal axis and utilize glucocorticoids as immune suppressive agents in control of peripheral inflammation

[0034] , The vagus also has a more direct effect on cells that mediate innate immunity. The efferent neurons of the vagus can release acetylcholine onto immune cells in the spleen (the major repository of cells mediating innate immunity) and suppress their activation. The vagal activity performing this function has been labeled the “Cholinergic Anti-inflammatory Pathway” (CAIP) since thePATENT transmitter mediating the anti-inflammatory effect of the vagus is acetylcholine

[0031] , It should be noted that the efferent component of the vagus nerve has several branches serving various organs, as well as an endogenous system serving the brain. In terms of the systemic immune response, there is a significant contribution of the splenic nerve which arises from the celiac ganglia in the mesentery and innervates the spleen and other organs

[0035] , Within the celiac plexus ganglia, efferent vagal terminals activate the splenic neurons to carry the stimulus to the spleen to suppress splenic macrophage activity and reduce the release of inflammatory cytokines

[0036] , Irrespective of the bifurcations of the vagal efferents leaving the brain, the efferent fibers of the vagus can be considered the mediators of the CAIP reflex and peripheral immune suppression when the immune system becomes pathologically active.

[0009] The sensing of peripheral immune overactivity', however, is also inherently important to the brain. Cytokines released by peripheral immune cells in response to pathogens can signal across the blood-brain barrier and activate the endogenous immune cells of the CNS, i.e., the microglia and astrocytes

[0037] , causing neuroinflammation. Interestingly, and as noted above, a vagal afferent component is also involved in control of brain neuroinflammation in pathological conditions. The main path for control of neuroinflammation by vagal sensory input into the CNS is the routing of the signal through the NTS and through second order neurons to the locus coeruleus (LC). The second order neurons from the NTS, synapsing on adrenergic neurons in the LC, in turn communicate with and activate cholinergic neurons in the Nucleus Basalis of Meynert (NBM) which also use acetylcholine to suppress overactivity' of brain microglia and astrocytes in various areas of brain

[0038] , What arises from analysis of the mechanisms by which the body controls the overactivity of the immune systems in both the periphery and the CNS is that cholinergic and noradrenergic mechanisms orchestrated by' the vagus nerve are critical for physiological suppression of the immune response in the brain as well as the periphery. It is also apparent that the sensory (afferent) portion of the vagus nerve plays a critical role in informing the CNS of the immune status in the periphery' and in initiating the proper responses to control the overactivity' of the immune system in the periphery as well as the CNS. The other important fact is that afferent vagal input into brain does not necessarily generate feedback to all areas of the body, and in terms of neuroinflammation, the component of signaling through the Nucleus Basalis of Meynert can serve as a modulator of the brain immune system without affecting the peripheral systems mediating the immune response. The distinction arises from the character of the subsets of vagal afferents activated by the peripheral stimulus and the selective activation of the second order neurons with cell bodies located in the NTS.PATENT

[0010] Given the major role played by the cholinergic system in down-regulating immune responses and the involvement of the a7 nicotinic cholinergic receptor (nAChR) in mediating this response

[0039] , current pharmacological thinking has also focused on modulating a7nAChR activity to obtain immunosuppression

[0040] , This strategy, when applied through peripheral drug administration, results in a number of untoward side effects

[0031] , Because of the off-target effects of a7nAChR agonists, efforts have been made to target the CAIP more directly using electrical stimulation of the vagus nerve (VNS) through implantable stimulating devices

[0041] , Some of the best evidence for the benefit of VNS as a therapeutic strategy has been in the area of CNS disorders (Table 2). VNS is approved by the FDA for treatment of medication-resistant depression and epilepsy

[0042] , VNS has also shown disease-modifying effects in a number of pre- clinical models [20, 38] of other CNS malfunction linked to neuroinflammation. In humans, the implantation of a vagal stimulatory device is not without adverse consequences, however

[0043] , and may not be suitable for treating conditions that require long-term immunomodulation. Transcutaneous (tc) stimulation of the vagus either by placing an electrode over the cervical vagus nerve in the neck (tc VNS) or the auricular branch of the vagus in the external ear (transauricular (ta) VNS) has been utilized to fill the need for a transient stimulation approach. This approach stimulates the afferent (sensory) vagus which, as mentioned above, activates secondary' neurons in the NTS, and this signal can be relayed either to the efferent vagus serving peripheral organs or to the Nucleus Basalis of Meynert for distribution throughout the brain. Transcutaneous vagal stimulation has demonstrated positive effects in animal models of endotoxemia

[0044] , and neuroprotective effects in models of Parkinson’s disease, post-operative cognitive dysfunction, traumatic brain injury, and ischemic stroke [21, 43, 45],

[0011] Overall, studies of vagal stimulation, including studies of stimulation of particular neurons of the afferent vagal system

[0046] , clearly demonstrate the potential of broad therapeutic application of vagal stimulation for control of systemic inflammation or neuroinflammatory conditions. However, electrical vagal stimulation is not a panacea for treatment of multiple disorders. Even transcutaneous stimulation requires clinical visits and the parameters (frequency, strength, etc.) of the stimulus are not well established [47, 48], The review by Kelly et al.

[0031] concludes with a statement that “Pharmacological manipulation of the CAIP remains somewhat elusive but warrants further study.” Thus, there is a need in the art for therapeutic agents that can act through the vagus nerve to activate the anti-inflammatory pathway, particularly in the brain, for treating neuroinflammation and other diseases and disorders. The disclosure is directed to this as well as other important ends.PATENTBRIEF SUMMARY

[0012] Provided herein are methods of treating neuroinflammation in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / |3‘ interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit or a y subunit. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I), Formula (II), Formula (A), or Formula (B).

[0013] Provided herein are methods of stimulating a vagus nerve in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit or a y subunit. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I), Formula (II), Formula (A), or Formula (B).

[0014] Provided herein are methods of treating or preventing a neuropathology' caused by neuroinflammation in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p- interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit or a y subunit. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I), Formula (II), Formula (A), or Formula (B).

[0015] Provided herein are methods of treating addiction, depression, anxiety, post-traumatic stress disorder, schizophrenia, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, a stroke, atraumatic brain injury, a spinal cord injury', a migraine, myalgic encephalomyelitis / chronic fatigue syndrome, or Gulf War syndrome in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / P‘ interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-APATENT receptors contain a 5 subunit or a y subunit. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I), Formula (II), Formula (A), or Formula (B).

[0016] These and other embodiments of the disclosure are described in detail herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows PAM effect of nezavist and its structural derivatives at the GABAA receptor. CM-113 is the ketone derivative of nezavist. and CM-116 and CM-117 are amide derivatives of nezavist. The effect of nezavist and its structural derivatives on submaximal ECio GABA currents of al[32y2- and al [325- containing GABAA receptors are demonstrated. Electrophysiological methods are described in Borghese et al. (1) GABA-A receptors were expressed in Xenopus oocytes. ***p<0.05, # p>0.05, compared to the PAM effect of nezavist.

[0018] FIGS. 2A-2B illustrate the effect of nezavist (FIG. 2A) and CM-113 (FIG. 2B) on alcohol self-administration by alcohol dependent rats. Male Wistar rats were trained to press a lever to self-administer alcohol, and another lever to self-administer water (operant responding). Once trained, the rats were made dependent on alcohol by chronic intermittent exposure to alcohol vapor in an alcohol inhalation chamber for 3 weeks, leading to the development of physical dependence as measured by various signs of alcohol withdrawal

[0049] , Alcoholdependent rats showed enhanced responding for alcohol compared to their pre-dependence baseline (ascertained prior to the chronic alcohol exposure). Nezavist and CM-113 were administered (ip) to rats, and operant responding for alcohol was measured beginning 30 minutes after an ip dose of nezavist or CM-113. Values represent the mean [±standard error of the mean (SEM)J number of rewards at the alcohol lever. ##, p<0.05 compared to baseline; **, p< 0.05, ***, p< 0.01, compared to control (0 nezavist).

[0019] FIG. 3 illustrates the effects of nezavist on dependence on nicotine. In this example the animals (rats) were made dependent on nicotine and nezavist was used to diminish the withdrawal / abstinence-induced increase in operant responding for nicotine. Adult male Sprague- Dawley rats were given extended access to nicotine self-administration using an escalating fixed ratio schedule

[0050] , After acquisition, rats were withdrawn from nicotine for eight days. Rats were injected ip with nezavist or vehicle 30 min prior to reacquisition sessions. The figure shows the effect of nezavist on active lever pressing and nicotine infusions during reacquisition of nicotine self-administration.

[0020] FIG. 4 illustrates the effect of nezavist in an animal model of major depressivePATENT disorder (learned helplessness [Porsolt Swim Test])

[0051] , This test is commonly used to measure effects of antidepressant drugs in rodents. The characteristic behavior of the test, termed immobility, develops when a rodent is placed in a tank (cylinder) of water for a period of time in which it cannot escape and stops attempting to escape and begins to make only the movements required to balance the body and float with its head above the water. In a pretest, 24 hr before the actual test, rats are placed into water-filled swim cylinders and removed after 15 min of swimming. To test the effects of nezavist, 24 hours after the pretest, vehicle and nezavist are administered by oral gavage 40 min prior to the 5-min immobility test. The latency to start floating and the amount of time spent trying to escape are measured. An antidepressant drug will increase the amount of time spent try ing to escape. The figure shows that the “floating time’' of female rats given nezavist was significantly decreased (i.e., time trying to escape was increased) compared to female rats given vehicle, i.e., nezavist had an “antidepressant” effect. *p< 0.03 (n=7 per group).

[0021] FIGS. 5A-5B illustrate vagus neuron firing rates and patterns. FIG. 5A: A subset of neurons has a mean interspike interval (Mil) of greater than 20 s when firing rates are measured under Krebs (control) conditions. FIG. 5B: A schematic of the vagal neuron firing pattern is shown and the terminology is illustrated: Mil: mean interspike interval, BD: burst duration, GD: gap duration, IBI: intraburst interval.

[0022] FIG. 6 illustrates the effect of nezavist on vagal firing rates measured in the ex vivo preparation of jejunum. To assess the effect of nezavist on single unit vagal fiber firing rate, the mean interspike interval (Mil) was measured. Fibers with rapid firing rates display shorter interspike intervals. Baseline recording with Krebs buffer was performed for 15 minutes, and then the luminal perfusate was switched for 40 minutes to one containing Krebs buffer plus nezavist. Nezavist at 10 pM significantly reduced the mean interspike interval, particularly of a subset of neurons with control Mil values of > 20 seconds (circled in blue). A decrease in Mil indicates an increase in the firing rate of these fibers.

[0023] FIG. 7 illustrates that nezavist reduces vagus neuron mean interspike interval (Mil) in a dose- dependent manner. The effect of nezavist on vagal nerve firing was evaluated at 1, 3,10 and 100 pM concentrations in the ex vivo jejunum system. Dose-response was evaluated using a Hill equation.

[0024] FIG. 8 illustrates that the GABA-A receptor antagonists, picrotoxin (channel blocker) and bicuculline (GABA competitive antagonist), inhibited the effect of nezavist on vagal firing in the ex vivo jejunum system. Firing rate is again defined as the mean interspike interval (Mil),PATENT i.e., a decrease in Mil indicates an increase in the firing rate of these fibers. 100 pM nezavist significantly increased the vagal firing rate, and this effect was blocked in the presence of 50 pM picrotoxin or 50 pM bicuculline. Picrotoxin and bicuculline alone had no significant effect on the control (Krebs) firing rate.

[0025] FIG. 9 illustrates the similarity or difference in vagal nen e firing pattern between nezavist, CCK, ethanol, and diazepam. Ethanol and diazepam were used as other examples of PAMs at the GABA-A receptor, but their actions are mediated through receptor sites different from those used by nezavist. Jejunal afferent firing patterns were measured in the presence of either 10 pM nezavist, 0.1 pM CCK, 1% ethanol, or 10 pM diazepam (recording methods described in West et al. (70)). Unlike nezavist, the GABA-A receptor PAM diazepam does not activate vagal fibers but the responses to nezavist and CCK are identical. Mil: mean interspike interval, BD: burst duration, GD: gap duration, IBI: intraburst interval. This differential effect of diazepam can be explained by the fact that the CCK-releasing enteroendocrine cells express GABA-A receptors containing a 5 subunit. Diazepam has no effect on 5 subunit-containing GABA-A receptors while nezavist acts as a potent PAM at these receptors. Activation of GABA-A receptors on CCK-releasing enteroendocrine cells results in an enhanced release of CCK

[0030] ,

[0026] FIGS. 10A-10C illustrate the effect of nezavist on the LPS-induced increase in c-Fos levels in areas of the nucleus tractus solitarius (NTS) receiving vagal input. We performed experiments in which mice were injected with LPS and 60 minutes later received nezavist i.p. The mice were sacrificed 18 hours after the nezavist injection, the brain was removed and sections were processed for quantification of c-Fos immunoreactivity in the NTS. FIG. 10A shows that the administration of nezavist after LPS reduced the number of cells in the anterior and posterior NTS that responded to LPS with an increase in c-Fos levels. FIG. 10B shows quantification of c-Fos positive cells in the anterior NTS at two time points after nezavist administration. FIG. 10C illustrates that the reduction in response to LPS by nezavist was particularly evident and statistically significant in the posterior (medio-caudal) NTS where the cell bodies of neurons that project to the locus coeruleus are located (the A2 adrenergic nucleus of the brainstem / NTS).

[0027] FIG. 11 illustrates the effect of nezavist on cytokine levels in hippocampus of rats treated chronically with LPS in the absence or presence of nezavist. Male C57BL / 6JRj mice (10 per group) were given ip injections of vehicle. LPS (0.5 mg / kg) / vehicle or LPS / nezavist (50 or 100 mg / kg) daily for 4 consecutive days. Nezavist was given 30 min after LPS. Animals werePATENT sacrificed on day 5, brains were removed, and the left hippocampus was homogenized and centrifuged to remove cell debris. Hippocampus extracts were analyzed for an inflammation panel using a U-PLEX custom cytokine assay. Data are expressed as pg / g protein. LPS treatment significantly increased the hippocampal levels of IL-1 (3, IL-6 and TNF-a and both doses of nezavist significantly reduced the LPS-induced increase in IL-ip. * p <0.03; *** p <0.001.

[0028] FIG. 12 illustrates quantification of Iba-1 hippocampal staining of mice treated with LPS and / or nezavist as described for FIG. 10. On day 5, brains were removed and the right hemi-brain was fixed by immersion in 4% paraformaldehyde in phosphate buffer for 2 hr at room temperature. Following fixation, brains were further processed and frozen brain samples were sectioned sagittally and sections were incubated with anti-Iba-1 antibodies, anti-GFAP antibodies and anti-CD68 antibodies followed by secondary antibodies. Iba-1 is a microglial marker

[0052] , GFAP as an astrocyte marker and CD68 is a marker for macrophages and monocytes. The figures show that Iba-1 staining (microglia) was significantly increased by LPS treatment. Nezavist at both doses (50 and 100 mg / kg daily for 4 days) led to a significant reduction in LPS-induced immunoreactive area, density and size values of Iba-1 positive objects, compared to LPS alone, suggesting reduced microgliosis in the nezavist-treated mice. The high dose of nezavist also reduced the LPS-induced increase in object intensity. * p<0.05; *** p<0.001. Additionally, LPS treatment significantly increased the number of microglia that displayed the Typel (activated) morphology

[0053] and nezavist reduced the number of LPS- activated microglia.DETAILED DESCRIPTION

[0029] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary’ skill in the art. See, e.g., Singleton et al.. Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this disclosure. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0030] The term '‘nezavisf ’ refers to a compound having the following structure:PATENTNezavist can be made by methods known in the art and described, for example, in US Patent No. 7,923,458, US Patent No. 10,112,905, and US Patent No. 10,453,371, the disclosures of which are incorporated by reference herein in their entirety7and for all purposes.

[0031] The term “CM-113” refers to a compound having the following structure:

[0032] The term “neuroinflammation” refers to an inflammatory response in the CNS. Generally, the inflammatory response is a chronic inflammatory response. The events involved in this chronic inflammatory response are mediated by the production of cytokines, chemokines, reactive oxygen species. Exemplary7cytokines involved in this chronic inflammatory7response include TNFa, IL-6, IL-1 (3, and MCP-1. The cytokines involved in this chronic inflammatory response are produced primarily by the microglia and astrocytes endogenous to the CNS.

[0033] Table 1 shows reports that provide evidence for neuroinflammation in psychiatric disorders, neurodegenerative diseases, and other neurological disorders.

[0034] Table 1PATENT

[0035] With reference to Table 1. the following abbreviations apply: TLR4: Toll-like receptor 4, IL-1R1: Interleukin 1 receptor type 1, IL-1|3: interleukin-1 beta, IL-6: interleukin-6, TGF-P: transforming grow th factor beta, HMGB1 : high mobility group box 1, TNFa: tumor necrosis factor alpha, IL -2: interleukin-2, IL-4: interleukin-4, bFGF: basic fibroblast growth factor, IL-1: interleukin- 1, PGD2: prostaglandin D2, NO: nitric oxide, CGRP: calcitonin gene-related peptide, IL-8: interleukin-8, CSF: cerebral spinal fluid, CXCL10: C-X-C motif chemokine ligand 10; MMP-9: matrix metalloprotease-9, HO-1 : heme oxygenase-1, IFN-y: interferon gamma, MCP-1 : monocyte chemoattractant protein-1, TSPO: translocator protein.

[0036] Table 2 provides reports on the role of vagal nerve stimulation (VNS) providingPATENT benefit in psychiatric disorders, neurodegenerative diseases, and other neurological disorders

[0037] Table 2PATENT

[0038] The term “etomidate” refers to the compound that is a modulator at GABA-A receptors containing (32 and (33 subunits.

[0039] The term “etomidate site of the GABA-A receptor” refers to the site in the GABA-A receptor that binds with etomidate. In embodiments, the etomidate site of the GABA-A receptor refers to the interface between the alpha (a") and beta ((3 ) subunits within the transmembrane domain of the GABA-A receptor.

[0040] The terms “treating” or “treatment” are used in accordance with their plain and ordinary meaning and broadly include any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission, whether partial or total and whether detectable or undetectable. Treatment may relieve the disease’s symptoms, fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things. Treatment methods include administering to a subject a therapeutically effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / (3‘ interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the term “treating” does not including preventing.

[0041] An “effective amount” is an amount sufficient to accomplish a stated purpose (e.g., achieve the effect for which it is administered, treat a disease). An example of an “effective amount” is an amount sufficient to contribute to the treatment or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).PATENTThe exact amounts will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques. In embodiments, “therapeutically effective amount” refers to the amount of the compound that is a positive allosteric modulator of GABA-A receptors binds to the a+ / p- interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor and that is sufficient to treat or ameliorate neuroinflammation.

[0042] The term “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. In embodiments, the administering does not include administration of any active agent other than the compound that is a positive allosteric modulator of GABA-A receptors binds to the a+ / p- interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor.

[0043] The terms “patient” or “subject” are used in accordance with its plain and ordinary meaning and refer to a living organism suffering from or prone to a disease that can be treated by administration of a compound that is a positive allosteric modulator of GABA-A receptors binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, cats, monkeys, and other non-mammalian animals. In embodiments, a patient is human patient.

[0044] The terms “expression level,” “amount,” or “level” of a biomarker (e.g., cytokine) is a detectable level in a biological sample. “Expression” generally refers to the process by which information (e.g., gene-encoded and / or epigenetic) is converted into the structures present and operating in the cell. Therefore, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide). Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide) shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., by proteolysis. “Expressed genes” includePATENT those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, miRNA, transfer RNA, ribosomal RNA, IncRNA). Expression levels can be measured by methods know n to one skilled in the art. The expression level or amount of a biomarker (e.g., RNA, miRNA) can be used to diagnose and / or treat a subject with a neuropathology caused by neuroinflammation.

[0045] The terms an “increased expression level’" or “increased level” of a biomarker (e.g., cytokine) is an expression level of the biomarker that is higher than the expression level of the biomarker in a healthy control (e.g., a subject that does not have a neuropathology caused by neuroinflammation). In embodiments, an “elevated expression level” of the biomarker compared to the control (when the expression level of the biomarker is greater than the corresponding control) is, for example, an increase in the expression level of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% or greater relative to the control. In embodiments, an “elevated expression level” of the biomarker is an amount that is statistically significantly greater than the expression level of the control.

[0046] “Biological sample” or “sample” refer to materials obtained from or derived from a subject or patient. A biological sample includes bodily fluids such as blood and blood fractions or products (e.g.. serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells, urine, and the like. In embodiments, a biological sample is blood. In embodiments, a biological sample is a serum sample (e.g., the fluid and solute component of blood without the clotting factors). In embodiments, a biological sample is a plasma sample (e.g., the liquid portion of blood).

[0047] The term “alkyl” as used herein is directed to a saturated hydrocarbon group (designated by the formula Cnhhn+i) which is straight-chained, branched or cyclized (“cycloalkyl”) and which is unsubstituted or substituted, i.e., has had one or more of its hydrogens replaced by another atom or molecule.[004S] “Aryl” designates either the 6-carbon benzene ring or the condensed 6-carbon rings of other aromatic derivatives (see, e.g., Hawley's Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley & Sons, Inc., New- York (1997)). Aryl groups include, without limitation, phenyl and naphthyl.

[0049] “Heteroaryl” rings are aromatic rings including at least one carbon atom in the ring and one or more, typically from 1-4, atoms forming the ring is an atom other than a carbon atom,PATENT i.e., a heteroatom (typically O, N or S). Heteroaryl includes, without limitation: morpholinyl, piperazinyl, piperidinyl, pyridyl, pyrrolidinyl, pyrimidinyl, triazinyl, furanyl. quinolinyl, isoquinolinyL thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, indolinyl, indolyl-4,7-dione, 1,2-dialkyl-indolyl, 1,2-dimethyl-indolyl, and l,2-dialkyl-indolyl-4, 7-dione.

[0050] “Alkoxy” means -OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy and the like.

[0051] “Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.

[0052] “Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.

[0053] “Halide” and “halo” refer to a halogen atom including fluorine, chlorine, bromine, and iodine.

[0054] Substituent groupings, e.g., Ci-6 alky l, are known, and are hereby stated, to include each of their individual substituent members, e.g., Ci alkyl, C2 alkyl, C3 alkyl and C4 alkyl.

[0055] “Substituted” means that one or more hydrogen atoms on the designated atom is / are replaced with a selection from the indicated group, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.

[0056] “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is, for example, “keto” then two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0057] Methods

[0058] Provided herein are methods of treating neuroinflammation in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / P" interface of GABA-A receptors. In embodiments, the GABA-A receptors do not contain a 5 subunit or a yPATENT subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y or 5 subunit. In embodiments, the neuroinflammation is chronic neuroinflammation. In embodiments, the patient has an increased expression level of a neuro inflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL- 1 (3, MCP-1, or a combination of two or more thereof.

[0059] Provided herein are methods of stimulating a vagus nerve in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / _interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the vagus nerve is a gastrointestinal vagal afferent. In embodiments, the patient has an increased expression level of an inflammatory cytokine in brain, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-ip, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0060] Provided herein are methods of treating a neuropathology caused by neuroinflammation in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p- interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the neuropathology is caused by chronic neuroinflammation. In embodiments, the neuropathology caused by neuroinflammation is a psychiatric disease, a neurological disease, stroke, traumatic brain injury.PATENT spinal cord injury, migraine, myalgic encephalomyelitis / chronic fatigue syndrome, or Gulf War syndrome. In embodiments, the neuropathology caused by neuroinflammation is depression, anxiety, post-traumatic stress disorder, schizophrenia, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, stroke, traumatic brain injury, spinal cord injury, migraine, myalgic encephalomyelitis / chronic fatigue syndrome, or Gulf War syndrome. In embodiments, the patient has an increased expression level of an inflammatory’ cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa. IL-6, IL- 1 , MCP-1. or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0061] Provided herein are methods of treating a psychiatric disease in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a 70" interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 8 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the psychiatric disease is caused by neuroinflammation. In embodiments, the psychiatric disease is depression, anxiety, post-traumatic stress disorder or schizophrenia. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory' cytokine is TNFa, IL-6, IL-10, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound ofPATENTFormula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0062] Provided herein are methods of treating depression in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the depression is major depressive disorder, persistent depressive disorder, or bipolar disorder. In embodiments, the depression is major depressive disorder. In embodiments, the depression is persistent depressive disorder. In embodiments, the depression is part of a bipolar disorder. In embodiments, the depression is treatment-resistant depression. See The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision. In embodiments, the patient has an increased expression level of an inflammatory cytokine in brain, relative to a healthy control. In embodiments, the neuroinflammalorv cytokine is TNFa. IL-6, IL-1 P, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0063] Provided herein are methods of treating anxiety in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / (3" interface of GABA- A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or ay subunit. In embodiments, the GABA-A receptorsPATENT contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the anxiety is generalized anxiety disorder. See The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-ip, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0064] Provided herein are methods of treating post-traumatic stress disorder in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 6 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the inflammatory cytokine is TNFa, IL-6, IL- 1 P, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (1) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).PATENT

[0065] Provided herein are methods of treating schizophrenia in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / 0‘ interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased expression level of an neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL- 1 , MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0066] Provided herein are methods of treating a neurological disease in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / 0" interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the neurological disease is Alzheimer’s disease, amyotrophic lateral sclerosis, or Parkinson’s disease. In embodiments, the patient has an increased expression level of an neuroinflammatory' cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-10, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically^ acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments,PATENT the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0067] Provided herein are methods of treating Alzheimer’s disease in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / " interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinfl ammatory cytokine, relative to a healthy control. In embodiments, the neuroinfl ammatory cytokine is TNFa, IL-6, IL-1 [3, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0068] Provided herein are methods of treating amyotrophic lateral sclerosis in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / 0" interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinfl ammatory cytokine, relative to a healthy control. In embodiments, the neuroinfl ammatory cytokine is TNFa, IL-6, IL-1 [3, MCP-1, or a combination of two or morePATENT thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0069] Provided herein are methods of treating Parkinson’s disease in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuromflammalorv cytokine, relative to a healthy control. In embodiments, the neuroinfl ammatory cytokine is TNFa, IL-6, IL-1 P, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein)

[0070] Provided herein are methods of treating a cognitive dysfunction in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / " interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. InPATENT embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 6 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the cognitive dysfunction is a post-operative cognitive dysfunction. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-1 (3, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0071] Provided herein are methods of treating a stroke in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA- A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the stroke is ischemic stroke. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-ip, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereofPATENT(including embodiments thereof as described herein).

[0072] Provided herein are methods of treating a traumatic brain injury' in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p- interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 6 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinfl ammatory cytokine, relative to a healthy control. In embodiments, the neuroinfl ammatory cytokine is TNFa, IL-6, IL-1 , MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0073] Provided herein are methods of treating a spinal cord injury' in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-1 P, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereofPATENT(including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0074] Provided herein are methods of treating a migraine in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / P" interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinfl ammatory cytokine is TNFa, IL-6, IL-1 P, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0075] Provided herein are methods of treating myalgic encephalomyelitis / chronic fatigue syndrome in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinfl ammatory cytokine, relative to a healthy control. In embodiments,PATENT the neuroinflammatory cytokine is TNFa, IL-6, IL-10, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0076] Provided herein are methods of treating Gulf War syndrome in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / 0" interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 6 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 6 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinflammatory' cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-10, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0077] Provided herein are methods of treating epilepsy in a patient in need thereof comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / 0" interfacePATENT of GAB A- A receptors and / or the etomidate site of the GAB A- A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit. In embodiments, the GABA-A receptors contain a y subunit. In embodiments, the patient has an increased brain expression level of a neuroinflammatory cytokine, relative to a healthy control. In embodiments, the neuroinflammatory cytokine is TNFa, IL-6, IL-1 (3, MCP-1, or a combination of two or more thereof. In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (A) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein). In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (B) or a pharmaceutically acceptable salt thereof (including embodiments thereof as described herein).

[0078] Compounds

[0079] Provided herein are compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / " interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor. In embodiments, the GABA-A receptors do not contain a 5 subunit or a y subunit. In embodiments, the GABA-A receptors contain a 5 subunit or a y subunit.

[0080] In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

[0081] In the compounds of Formula (I), R1is H, C2-C4 alkyl, C2-C4 alkenyl, halogen, ZXR9,PATENT or N(R10)(Rn). In embodiments, R1is H, C2-C4 alkyl, C2-C4 alkenyl, halo, Z'R9, orN(R10)(Rn). In embodiments, R1is H. In embodiments, R1is C2-C4 alkyl. In embodiments, R1is C2-C4 alkenyl. In embodiments, R1is halogen. In embodiments, R1is ZXR9. In embodiments, R1is N(R10)(Rn).

[0082] In the compounds of Formula (I), R2is H, C1-C4 alkyl, C2-C4 alkenyl, halogen, Z2R12, N(R13)(R14), or C1-C4 alky l substituted with one or more moiety selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, halo, Z3R15, and N(R16)(R17). In embodiments, R2is H

[0083] In the compounds of Formula (I), R3, R4, R5, and R6are each independently H, C1-C4 alkyl, C2-C4 alkenyl, halogen, -NO2, Z3R18, or N(R19)(R20). In embodiments, R4and R6and hydrogen and R3and R5are each independently H, C1-C4 alkyl. C2-C4 alkenyl, halogen, -NO2. ZJR18, or N(R19)(R20). In embodiments, R4and R6and hydrogen and RJand R5are each independently C1-C4 alkyl, C2-C4 alkenyl, halogen, -NO2, Z3R18, or N(R19)(R20). In embodiments, R4and R6and hydrogen and R1and R5are each independently halogen. In embodiments, R4and R6and hydrogen and R3and R5are each independently -F. -Cl, -Br, or -I. In embodiments, R4and R6and hydrogen and R3and R5are each independently -F, -Cl, or -Br. In embodiments, R4and R6and hydrogen and R3and R5are each independently -F or -Cl. In embodiments, R4and R6and hydrogen and R3and R5are -F. In embodiments, R4and R6and hydrogen and R3and R5are -Cl.

[0084] In the compounds of Formula (I), X1is N or CH. In embodiments, X1is N. In embodiments, X1is CH.

[0085] In the compounds of Formula (I), R7and R8are each independently H, Ci-Ce alkyl, C2- C4 alkenyl, C2-C4 alkynyl, aryl, or Ci-Cg alkyl substituted with one or more moiety selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, nitro, halo, Z4R21, and N(R22)(R23); or R7and R8together with X1form a 5 to 8 member saturated, unsaturated, or aromatic organic cyclic or heterocyclic moiety. In embodiments, R7and R8are each independently H, Ci-Ce alkyl, C2-C4 alkenyl. C2-C4 alkynyl, aryl, or Ci-Cg alkyl substituted with one or more moiety selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, nitro, halo, Z4R21, and N(R22)(R23). In embodiments, R7and R8together with X1form a 5 to 8 member saturated, unsaturated, or aromatic organic cyclic or heterocyclic moiety. In embodiments, R7and R8are each independently Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, or Ci-Cg alkyl substituted with one or more moiety selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, nitro, and halogen. In embodiments, R7and R8are each independently aryl. In embodiments, the aryl is phenyl, tolyl, xylyl, or naphthyl. In embodiments, R7and R8are phenyl.PATENT

[0086] In the compounds of Formula (I), R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22. and R23are each independently H. C1-C4 alkyl, or C1-C4 alkyl substituted with one or more moiety selected from the group consisting of Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, heteroaryl, Z5R24, and N(R25)(R26). In embodiments, R9is H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more moiety selected from the group consisting of Ci-Ce alky l, C2-C4 alkenyl, C2-C4 alkynyl, halo, heteroaryl, Z5R24, and N(R25)(R26). In embodiments, R9is H. In embodiments, R9is C1-C4 alkyl. In embodiments, R9is Ci alkyl. In embodiments, R9is C2 alkyl. In embodiments, R9is C3 alkyl. In embodiments, R9is C4 alkyl. In embodiments, R10and R11are each independently H or C1-C4 alkyl. In embodiments, R10and R11are H. In embodiments, R10and R11are each independently C1-C4 alkyl. In embodiments, R10and R11are each independently C1-C3 alkyl. In embodiments, R10and R11are each independently C1-C2 alkyl.

[0087] In the compounds of Formula (I), Z1, Z2. Z3. Z4, and Z5are each independently -O-, -S, -NH-, -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-. In embodiments, Z1, Z2, Z3, Z4, and Z5are each independently -O-, -S, or -NH-. In embodiments, Z1, Z2, Z3, Z4, and Z5are each independently -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH- In embodiments, Z1, Z2, Z3, Z4, and Z5are each independently -C(=O)O-, -OC(=O)-, or -C(=O)-. In embodiments, Z1, Z2, Z1, Z4, and Z5are each independently -C(=O)O- or -OC(=O)-. In embodiments, Z1, Z2, Z3, Z4. and Z5are each -C(=O)O- In embodiments, Z1, Z2, Z3, Z4, and Z5are each -OC(=O)-. In embodiments, Z1, Z2, Z3, Z4, and Z5are each -C(=O)-.

[0088] In the compounds of Formula (I), R24, R25, and R26are each independently C1-C4 alkyl.

[0089] In embodiments, the compound of Formula (I) is in the freebase form. In embodiments, the compound of Formula (I) is in the form of a pharmaceutically acceptable salt.

[0090] In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:

[0091] In the compounds of Formula (II), R1is H, C2-C4 alkyl, C2-C4 alkenyl, halogen, Z'R9, or N(R10)(Rn). In embodiments. R1is H, C2-C4 alkyd. C2-C4 alkenyl, halo, Z'R9, orN(R10)(Rn).PATENTIn embodiments, R1is H. In embodiments, R1is C2-C4 alkyl. In embodiments, R1is C2-C4 alkenyl. In embodiments, R1is halogen. In embodiments, R1is ZXR9. In embodiments, R1is NCR^XR11).

[0092] In the compounds of Formula (II). R3and R5are each independently H. C1-C4 alkyl, C2-C4 alkenyl, halo, -NO2, Z3R18, or N(R19)(R20). In embodiments, R3and R5are each independently C1-C4 alkyl, C2-C4 alkenyl, halogen, -NO2, Z3R18, or N(R19)(R20). In embodiments, R3and R5are each independently halogen. In embodiments, R3and R5are each independently -F, -Cl, -Br. or -I. In embodiments, R3and R5are each independently -F, -Cl, or - Br. In embodiments, R3and R5are each independently -F or -Cl. In embodiments, R3and R5are -F. In embodiments, R3and R5are -Cl.

[0093] In the compounds of Formula (II), R7and R8are each independently H, Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, ary l . or Ci-Ce alkyd substituted with one or more moiety7selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, nitro, halo, Z4R21, and N(R22)(R23); or R7and R8together with X1form a 5 to 8 member saturated, unsaturated, or aromatic organic cyclic or heterocyclic moiety7. In embodiments, R7and R8are each independently H, Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or ary l. In embodiments, R7and R8are each independently Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, or Ci-Ce alkyl substituted with one or more moiety selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, nitro, and halogen. In embodiments, R7and R8are each independently aryl. In embodiments, the aryl is phenyl, tolyl, xylyl, or naphthyl. In embodiments, R7and R8are phenyl.

[0094] In the compounds of Formula (II), R9, R10, R11, R18, R19, R20, R21, R22, and R23are each independently H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more moiety' selected from the group consisting of Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, heteroary l, Z5R24, and N(R25)(R26). In embodiments, R9is H. C1-C4 alkyl, or C1-C4 alkyl substituted with one or more moiety selected from the group consisting of Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, heteroary l, Z5R24, and N(R25)(R26). In embodiments, R9is H. In embodiments, R9is C1-C4 alkyl. In embodiments, R9is Ci alkyl. In embodiments, R9is C2 alky l. In embodiments, R9is C3 alkyl. In embodiments, R9is C4 alkyl. In embodiments, R10and R11are each independently H or C1-C4 alkyl. In embodiments, R10and R11are H. In embodiments, R10and R11are each independently C1-C4 alkyl. In embodiments, R10and R11are each independently C1-C3 alkyl. In embodiments, R10and R11are each independently C1-C2 alky l.

[0095] In the compounds of Formula (II), Z1, Z3, Z4, and Z5are each independently -O-, -S, - NH-, -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-. In embodiments, Z1, Z3, Z4, and Z5arePATENT each independently -0-, -S, or -NH-. In embodiments, Z1, Z3, Z4, and Z5are each independently -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-. In embodiments, Z1, Z3, Z4, and Z5are each independently -C(=O)O-, -OC(=O)-, or -C(=O)-. In embodiments, Z1, Z3, Z4, and Z5are each independently -C(=O)O- or -OC(=O)-. In embodiments, Z1, Z3, Z4, and Z5are each -C(=O)O-. In embodiments, Z1, Z3, Z4, and Z5are each -OC(=O)-. In embodiments, Z1, Z3, Z4, and Z5are each -C(=O)-.

[0096] In the compounds of Formula (II), R24, R25, and R26are each independently is C1-C4 alkyl.

[0097] In embodiments of the compounds described herein, R1is ZXR9; R3and R5are independently H. C1-C4 alkyl, C2-C4 alkenyl, halogen, or -NO2; R7and R8are each independently Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or phenyl; R9is H or Ci-Ce alkyl; and Z1is -C(=O)O-, -OC(=O)-, or -C(=O)-.

[0098] In embodiments of the compounds described herein, R1is ZlR9X1is N; R9is H or Ci- 4 alkyl; and Z1is -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-. In embodiments of the compounds described herein, R1is ZXR9; X1is N; R7is phenyl; R8is phenyl; R9is C1-4 alkyl; and Z1is -C(=O)O-, -OC(=O)-, or -C(=O)-. In embodiments of the compounds described herein, R1is Z R9X1is N; R7is phenyl; R8is phenyl; R9is C1-4 alkyl; and Z1is -C(=O)O-. In embodiments of the compounds described herein, R1is ZlR9X1is N; R7is phenyl; R8is phenyl; R9is C1-4 alkyl; and Z1is -C(=O)-.

[0099] In embodiments, the compound of Formula (II) is in the freebase form. In embodiments, the compound of Formula (II) is in the form of a pharmaceutically acceptable salt.

[0100] In embodiments, the compound that is a positive allosteric modulator of GABA-A receptors is a compound of Formula (III) or a pharmaceutically acceptable salt thereof:wherein Z1is -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-; R3is halogen; R4is halogen; and R9is H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more moiety selected from the groupPATENT consisting of Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, heteroaryl, Z5R24, and N(R25)(R26); wherein Z5. R24, R25, and R26are as defined for the compound of Formula (I). In embodiments, Z1is -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-; R3is halogen; R4is halogen; and R9is H or C1-C4 alkyl. In embodiments, Z1is -C(=O)O- or -C(=O)-; R3is halogen; R4is halogen; and R9is C1-C4 alkyl. In embodiments, Z1is -C(=O)O- and R9is C1-C4 alky l. In embodiments, Z1is -C(=O)O- and R9is Ci alkyl. In embodiments, Z1is -C(=O)O- and R9is C2 alkyl. In embodiments, Z1is -C(=O)O- and R9is C3 alkyl. In embodiments, Z1is -C(=O)O- and R9is C4 alkyl. In embodiments, Z1is -C(=O)- and R9is C1-C4 alkyl. In embodiments, Z1is - C(=O)- and R9is Ci alkyl. In embodiments, Z1is -C(=O)- and R9is C2 alkyl. In embodiments, Z1is -C(=O)- and R9is C3 alky l. In embodiments, Z1is -C(=O)- and R9is C4 alkyl. In embodiments, R3and R5are each independently-F, -Cl, -Br, or -I. In embodiments, R3and R5are each independently -F, -Cl, or -Br. In embodiments, R3and R5are each independently -F or -Cl. In embodiments, R3and R5are -F. In embodiments, R' and R5are -Cl. In embodiments, the compound of Formula (III) is in the freebase form. In embodiments, the compound of Formula (III) is in the form of a pharmaceutically acceptable salt.

[0101] In embodiments, the compound of Formula (I) is a compound of Formula (A) or a pharmaceutically acceptable salt thereof:In embodiments, the compound of Formula (A) is in the freebase form. In embodiments, the compound of Formula (A) is in the form of a pharmaceutically acceptable salt. In embodiments, the compound of Formula (A) is in the form of a toluene sulfonic acid salt.

[0102] In embodiments, the compound of Formula (I) is a compound of Formula (B) or a pharmaceutically acceptable salt thereof:PATENTIn embodiments, the compound of Formula (B) is in the freebase form. In embodiments, the compound of Formula (B) is in the form of a pharmaceutically acceptable salt.

[0103] “Pharmaceutically acceptable,” when used in reference to salts or carriers, refer to materials that are generally accepted as being suitable for administration to or contact with the human body or portions thereof. Pharmaceutically acceptable salts are materials in which the parent compound (e.g., a compound of Formula (I)) is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, or alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic. fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Pharmaceutically acceptable salts are those forms of compounds, suitable for use in contact with the tissues of human beings and animals without causing excessive toxicity, irritation, allergic response, or other problems or complication, commensurate with a reasonable benefit / risk ratio.

[0104] Pharmaceutically acceptable salt forms of the compounds described herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts arePATENT found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is incorporated herein by this reference.

[0105] Pharmaceutical Compositions

[0106] Any of the compounds described herein may be administered to a subject in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. The compositions are suitable for formulation and administration in vitro or in vivo. Suitable carriers and excipients and their formulations are known in the art and described, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed, Lippicott Williams & Wilkins (2005).

[0107] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethy cellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful.

[0108] In embodiments, the pharmaceutical compositions include, but are not limited to, those forms suitable for oral, rectal, nasal, topical, (including buccal and sublingual), transdermal, vaginal, parenteral (including intramuscular, intraperitoneal, subcutaneous, and intravenous), spinal (epidural, intrathecal), and central (intracerebroventricular) administration. The compositions can, where appropriate, be conveniently provided in discrete dosage units. The pharmaceutical compositions can be prepared by any of the methods well known in the pharmaceutical arts. In embodiments, the modes of administration include oral, intravenous (iv), topical, and subcutaneous.

[0109] Pharmaceutical formulations suitable for oral administration include capsules, cachets, or tablets, each containing a predetermined amount of one or more of the aminoquinoline compounds, as a powder or granules. In embodiments, the oral composition is a solution, aPATENT suspension, or an emulsion. In embodiments, the compounds can be provided as a bolus, electuary, or paste. Tablets and capsules for oral administration can contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, colorants, flavoring agents, preservatives, or wetting agents. In embodiments, the tablets can be coated according to methods well known in the art. Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. In embodiments, the compositions can be provided as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and the like. The additives, excipients, and the like typically will be included in the compositions for oral administration within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art. The compounds described herein will be included in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and pharmaceutical arts.

[0110] Pharmaceutical compositions for parenteral or central administration (e g., by bolus injection or continuous infusion) can be provided in unit dose form in ampoules, pre-filled syringes, small volume infusion, or in multi-dose containers, and can include an added preservative. The compositions for parenteral administration can be suspensions, solutions, or emulsions, and can contain excipients such as suspending agents, stabilizing agents, and dispersing agents. In embodiments, the compounds can be provided in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. The additives, excipients, and the like typically will be included in the compositions for parenteral administration within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art. The compounds described herein will be included in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and pharmaceutical arts.[OHl] Pharmaceutical compositions for topical administration of the compounds to the epidermis (mucosal or cutaneous surfaces) can be formulated as ointments, creams, lotions, gels, or as a transdermal patch. Such transdermal patches can contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol, t-anethole, and the like. Ointments and creams can, for example, include an aqueous or oily base with the addition of suitable thickening agents,PATENT gelling agents, colorants, and the like. Lotions and creams can include an aqueous or oily base and typically also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, coloring agents, and the like. Gels can include an aqueous carrier base and include a gelling agent such as cross-linked polyacrylic acid polymer, a derivatized polysaccharide (e.g., carboxymethyl cellulose), and the like. The additives, excipients, and the like typically will be included in the compositions for topical administration to the epidermis within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art.

[0112] Pharmaceutical compositions suitable for topical administration in the mouth (e.g., buccal or sublingual administration) include lozenges comprising the aminoquinoline compound in a flavored base, such as sucrose, acacia, or tragacanth; pastilles comprising the aminoquinoline compound in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. In embodiments, the pharmaceutical compositions for topical administration in the mouth can include penetration enhancing agents. The additives, excipients, and the like typically will be included in the compositions of topical oral administration within a range of concentrations suitable for their intended use or function in the composition, and which are well known in the pharmaceutical formulation art.

[0113] In embodiments, the pharmaceutical compositions are suitable for intra-nasal administration. Such intra-nasal compositions comprise a compound described herein in a vehicle and suitable administration device to deliver a liquid spray, dispersible pow der, or drops. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents, or suspending agents. Liquid sprays are conveniently delivered from a pressurized pack, an insufflator, a nebulizer, or other convenient means of delivering an aerosol comprising the peptide. Pressurized packs comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas as is well known in the art. Aerosol dosages can be controlled by providing a valve to deliver a metered amount of the peptide. In embodiments, pharmaceutical compositions for administration by inhalation or insufflation can be provided in the form of a dry pow der composition, for example, a pow der mix of the aminoquinoline compound and a suitable powder base such as lactose or starch. Such powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin packs, or blister packs, from which the powder can be administered w ith the aid of an inhalator or insufflator.PATENT

[0114] In embodiments, the pharmaceutical compositions of the present invention can include one or more other therapeutic agent, e.g., as a combination therapy. The additional therapeutic agent will be included in the compositions within a therapeutically useful and effective concentration range, as determined by routine methods that are well known in the medical and pharmaceutical arts. The concentration of any particular additional therapeutic agent may be in the same range as is typical for use of that agent as a monotherapy, or the concentration may be lower than a typical monotherapy concentration if there is a synergy when combined with compound described herein. For example, the compounds described herein can be administered in conjunction with an antidepressant or anti-anxiety agent for treating psychiatric disorders. In embodiments, the compound described herein can be administered in conjunction with an antimigraine agent (e.g.. sumatriptan, rizatriptan) for treating a migraine.

[0115] Dose and Dosing Regimens

[0116] The dosage (single or multiple doses) of the compounds described herein and frequency of administration (e.g., QD. BID) of the compounds described herein can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Adjustment and manipulation of established dosages (e.g., frequency and duration) are within the ability of the skilled artisan.

[0117] For any composition and compound described herein, the effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of compounds that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. As is known in the art, effective amounts of compounds for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0118] Dosages of the compounds may be varied depending upon the requirements of the patient. The dose administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence,PATENT nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the art. Dosage amounts and intervals can be adjusted individually to provide in vivo levels of the compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the disease state.

[0119] In embodiments, the compounds described herein are administered to a patient at an amount of about 1.0 mg / kg to about 200 mg / kg. It is understood that where the amount is referred to as “mg / kg, " the amount is milligram per kilogram body weight of the subject being administered with the compound described herein. In embodiments, the compounds described herein are administered to a 60 kg patient in an amount from about 60 mg to about 12 mg per day.

[0120] Embodiments 1-39

[0121] Embodiment 1. A method of treating neuroinflammation in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p- interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor.

[0122] Embodiment 2. The method of Embodiment 1, wherein the neuroinflammation is chronic neuroinflammation.

[0123] Embodiment 3. A method of stimulating a vagus nerve in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / 0" interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor.

[0124] Embodiment 4. A method of treating a neuropathology caused by neuroinflammation in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor.

[0125] Embodiment 5. The method of Embodiment 4, wherein the neuroinflammation is chronic neuroinflammation.

[0126] Embodiment 6. The method of Embodiment 4 or 5, wherein the neuropathology7is a psychiatric disease.PATENT

[0127] Embodiment 7. The method of Embodiment 6, wherein the psychiatric disease is depression.

[0128] Embodiment 8. The method of Embodiment 6, wherein the psychiatric disease is anxiety.

[0129] Embodiment 9. The method of Embodiment 6, wherein the psychiatric disease is post- traumatic stress disorder.

[0130] Embodiment 10. The method of Embodiment 6. wherein the psychiatric disease is schizophrenia.

[0131] Embodiment 11. The method of Embodiment 4 or 5, wherein the neuropathology is a neurological disease.

[0132] Embodiment 12. The method of Embodiment 11, wherein the neurological disease is Alzheimer’s disease.

[0133] Embodiment 13. The method of Embodiment 11, wherein the neurological disease is amyotrophic lateral sclerosis.

[0134] Embodiment 14. The method of Embodiment 11, wherein the neurological disease is Parkinson’s disease.

[0135] Embodiment 15. The method of Embodiment 4 or 5, wherein the neuropathology is a stroke.

[0136] Embodiment 16. The method of Embodiment 4 or 5, wherein the neuropathology is a traumatic brain injury.

[0137] Embodiment 17. The method of Embodiment 4 or 5, wherein the neuropathology is a spinal cord injury.

[0138] Embodiment 18. The method of Embodiment 4 or 5, wherein the neuropathology is a migraine.

[0139] Embodiment 19. The method of Embodiment 4 or 5, wherein the neuropathology is myalgic encephalomyelitis / chronic fatigue syndrome.

[0140] Embodiment 20. The method of Embodiment 4 or 5, wherein the neuropathology is Gulf War syndrome.

[0141] Embodiment 21. The method of any one of Embodiments 1 to 20, wherein the patient has an increased expression level of an inflammatory cytokine, relative to a healthy control.PATENT

[0142] Embodiment 22. The method of Embodiment 21, wherein the inflammatory cytokine is TNFa, IL-6, IL- 1 , MCP-1, or a combination of two or more thereof.

[0143] Embodiment 23. The method of Embodiment 21, wherein the inflammatory cytokine is IL-ip.

[0144] Embodiment 24. The method of any one of Embodiments 1 to 23. wherein the administering is peripherally administering.

[0145] Embodiment 25. The method of any one of Embodiments 1 to 24. wherein the GABA-A receptors do not contain a 5 subunit or a y subunit.

[0146] Embodiment 26. The method of any one of Embodiments 1 to 24, wherein the GABA-A receptors contain a 5 subunit.

[0147] Embodiment 27. The method of any one of Embodiments 1 to 24, wherein the GABA-A receptors contain a y subunit.

[0148] Embodiment 28. The method of any one of Embodiments 1 to 27, wherein the compound that is the positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:Wherein R1is H. C2-C4 alkyl, C2-C4 alkenyl, halogen. ZXR9, or N(R10)(Rn); R2is H. C1-C4 alkyl, C2-C4 alkenyl, halogen, Z2R12, N(R13)(R14), or C1-C4 alkyl substituted with one or more moiety selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, halogen, Z3R15, and N(R16)(R17); R3, R4, R5, and R6are each independently H, C1-C4 alkyl, C2-C4 alkenyl, halogen, - NO2, Z3R18, or N(R19)(R20); X1is N or CH; R7and R8are each independently H, Ci-Cg alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, or Ci-Ce alkyl substituted with one or more moiety selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, nitro, halogen, Z4R21, and N(R22)(R23); or R7and R8together with X1form a 5 to 8 member saturated, unsaturated, or aromatic organic cyclic or heterocyclic moiety; R9, R10, R11, R12, R13. R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23are each independently H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or morePATENT moiety selected from the group consisting of Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen, heteroaryl, Z5R24, and N(R25)(R26); Z1, Z2. Z3. Z4, and Z5are each independently -O-, -S, -NH-, - C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-; and R24, R25, and R26are each independently is C1-C4 alkyl.

[0149] Embodiment 29. The method of Embodiment 28, wherein the compound of Formula (I) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:

[0150] Embodiment 30. The method of Embodiment 29, where R1is Z1R9; R3and R5are independently H, C1-C4 alkyl, C2-C4 alkenyl, halogen, or -NO2; R7and R8are each independently Ci-Ce alkyl. C2-C4 alkenyl, C2-C4 alkynyl, or phenyl; R9is H or Ci-Ce alkyl; Z1is -C(=O)O-, -OC(=O)-, or -C(=O)-.

[0151] Embodiment 31. method of any one of Embodiments 28 to 30, wherein R3and R5are independently halogen.

[0152] Embodiment 32. The method of any one of Embodiments 28 to 31, wherein R7and R8are phenyl.

[0153] Embodiment 33. The method of any one of Embodiments 28 to 32, wherein R1is Z4R9; Z1is -C(=O)- and R9is Ci-Ce alkyl.

[0154] Embodiment 34. The method of any one of Embodiments 28 to 32, wherein R1is Z4R9; Z1is -C(=O)O- and R9is C1-C4 alkyl.

[0155] Embodiment 35. The method of Embodiment 28, wherein the compound of Formula(I) is a compound of Formula (A) or a pharmaceutically acceptable salt thereof:PATENT

[0156] Embodiment 36. The method of Embodiment 28, wherein the compound of Formula(I) is a compound of Formula (B) or a pharmaceutically acceptable salt thereof:

[0157] Embodiment 37. A compound of Formula (A) or a pharmaceutically acceptable salt thereof:

[0158] Embodiment 38. A compound of Formula (B) or a pharmaceutically acceptable salt thereof:PATENT

[0159] Embodiment 39. A compound of Formula (C) or a pharmaceutically acceptable salt thereof:EXAMPLES

[0160] Example 1

[0161] GABA acts as an inhibitory transmitter in brain, but in the intestine can act to depolarize, and activate neurons

[0094] , GABA acts through canonical GABA-A receptors to generate its neuron activating function in the gut

[0095] , but the chloride gradient across cell membranes in the gut produces a depolarizing event upon the opening of the GABA-A receptor chloride channel. GABA-A receptor subunits have been identified in various cells of the gut, and GABA and agonists acting at the GABA-A receptor have been shown to produce physiological responses including gut motor neuron depolarization and hormone release [30, 96], The source of GABA in the intestine is the enteric nervous system neurons, and GABA is also a product of the gut microbiota including bacteria such as lactobacillus rhamnosus [97 J. The application of lactobacillus rhamnosus (Strain JB1) to the luminal surface of the jejunum was show n to produce an increase in firing of vagal afferent neurons

[0029] , and to activate second order neurons residing in the NTS (using an increase in cFos as a marker of activation)

[0098] , Furthermore, a one-week treatment of mice with lactobacillus rhamnosus was shown to alter the expression of GABA-A receptor subunits in brain

[0099] , Thus, it has been stated that activation ofPATENTGABA-A receptors in the gut can generate signals to brain and produce changes in short and long-term brain function.

[0162] We have earlier described and patented a new chemical entity and its chemical derivatives that act as positive allosteric modulators (PAMs) of GABA action at the GABA-A receptor [100, 101], This molecule (nezavist) and certain of its derivatives are unique due to their binding site on the GABA-A receptor which is located between the a+and 0" extracellular faces of the GABA-A receptor subunits and / or the etomidate site of the GABA-A receptor. These molecules are also unique due to the fact that they can act as positive allosteric modulators (PAMs) of GABA-A receptors containing 5, as well as y subunits

[0100] , We have recently found that the ketone derivative (CM113) of nezavist has effects at the GABA-A receptor which are similar to that of nezavist itself. FIG. 1 illustrates the effects of these compounds on electrophysiological measures of the GABA-A receptor action. Interestingly, amide derivatives (CM116 and CM117) of nezavist, which would be expected to best resemble the ester moiety in nezavist, showed no PAM activity at the GABA-A receptor. Additionally, nezavist can block the escalation of ethanol drinking seen in alcohol-dependent animals

[0101] and (FIG. 2A). and CM-113 produces the same effect as nezavist on alcohol consumption (FIG. 2B). Thus, the modification of the substitution on the Cl position of nezavist from an ester to a ketone generates compounds comparable to nezavist in their biological and behavioral effects. The most well-studied PAMs of GABA-A receptors to this point are the benzodiazepines

[0102] but these molecules, and the imidazopyri dines (e.g., zolpidem), bind to a site between the a+and y subunits, and do not function with 5 subunit-containing GABA-A receptors

[0102] , This point becomes important when comparing benzodiazepine pharmacology to that of nezavist. We have now discovered that nezavist, acting through the GABA-A receptor, can activate a subset of vagal nerve neurons which innervate the gut, and thereby provide signals to brain that can abrogate neuroinflammation.

[0163] Example 2

[0164] As described earlier, a novel chemical entity, nezavist, as well as some of its derivatives act as positive allosteric modulators of GABA at particular GABA-A receptors. GABA-A receptors are distributed throughout the body, but access to these receptors depends on the pharmacokinetic properties of the pharmaceutical compound. These pharmacokinetic properties are determined by the physical features of the compound and its metabolism in the organism. An important pharmacokinetic feature of the actions of nezavist is that it does not appear in brain after peripheral administration (Tables 3 and 4) and thus if it produces effects inPATENT the CNS, these effects must be communicated to brain from events that take place in the periphery. To ascertain the pharmacokinetic parameters for nezavist, we examined blood and tissue levels of nezavist after intraperitoneal (i.p.) and oral (p.o.) administration. In in vitro studies with liver homogenates, we found a rapid disappearance of nezavist added to the liver tissue, and we noted low levels of circulating nezavist after oral (p.o.) administration in vivo, indicating a robust first pass metabolism of nezavist through the liver. What was notable was that little or no nezavist was found either in blood or in brain tissue after oral administration (Tables 3 and 4). Similar results were obtained after intraperitoneal administration of nezavist. The lack of nezavist in the brain was supported by data on the CNS effects of nezavist. There was no evidence of sedation, anxiolysis or incoordination, or of behavioral / physiological effects measured in the Irwin battery of tests, in animals given high doses of nezavist (these behavioral effects would be expected from a GABA-A receptor PAM acting within brain). On the other hand, our early studies on the ability of nezavist to prevent relapse in alcohol-dependent animals produced positive results (FIG. 2A). Furthermore nezavist, administered i.p. reduced nicotine self-administration by animals that were dependent on nicotine (FIG. 3) Our studies also showed that orally administered nezavist acts as an antidepressant in a rat model of “learned helplessness” (FIG. 4). These results indicated that nezavist could act via a peripheral mechanism to produce effects on certain CNS-mediated behaviors.

[0165] Nezavist blood and brain levels were determined after oral administration of nezavist (50 or 150 mg / kg) to male Sprague Dawley rats. Nezavist was administered as a suspension in 5% DMSO, 5% Emulphor, and 90% sterile water. Whole blood and brain samples were collected at 0.5, 1, 1.5, and 2 hrs post dose and analyzed by LC-MS / MS for quantification of nezavist. BQL = below the limit or quantitation. NC = sample not collected. Blood: n=3-9 / time point; BQL < 1 ng / ml (2.2 nM) Brain: n = 3 / time point; BQL < 7.5 ng / g (16 nM). The results are shown in Tables 3 and 4.

[0166] Table 3PATENT

[0167] Table 4

[0168] Example 3

[0169] GABA is present in the intestine and can directly or indirectly activate the afferent vagal neurons. We postulate that nezavist would be expected to significantly potentiate the GABA effect and potentiate the firing of these afferent neurons. To investigate nezavist actions on vagal nerve electrophysiology we employed an approach and protocol described by

[0029] in which single fiber vagal neuron discharge rates are measured in an in vitro preparation of mouse jejunum. The trunk of the vagal nerve exiting the jejunum is separated into singular fibers (neuron axons) and the action potentials traveling the neuronal axons under basal (control) conditions, or after drug perfusion on the luminal side of the intestinal segment, are recorded. The data are then analyzed to capture the chronological features of the neuron firing patterns (e.g., mean interspike interval [the shorter the interval the more rapid the firing]; burst duration, etc.) (FIGS. 5A-5B).

[0170] FIG. 6 illustrates the pattern of particular fibers recorded under control condition (Krebs buffer perfused jejunum) versus recording when 10 pM nezavist was perfused through the jejunum. What is notable in these data is that nezavist stimulates the rate of discharge of a subset of neurons which, under the control ("Krebs buffer”) condition, have a particularly slow rate of firing. FIG. 7 illustrates the dose-dependence of this effect of nezavist. All of the recorded neurons are assumed to be afferent (traveling from gut to brain). Efferent neuron axons (fibers) would be quiescent, since they have been severed from the components that can generate an action potential in response to a chemical stimulus (which reside in the CNS). Our data, discussed above, demonstrated that nezavist is a PAM at GABA-ARs and, if GABA-ARs are involved in the response noted in the firing patterns of the afferent vagal neurons, then a known GABA-AR channel blocker, picrotoxin

[0103] , or a GAB A- AR binding site antagonist, bicuculline

[0104] , would be expected to dampen or eliminate the response to nezavist. FIG. 8 illustrates the effect of picrotoxin and bicuculline on the firing response of vagal afferents exposed to nezavist when the jejunum was perfused with picrotoxin or bicuculline. Picrotoxin and bicuculline completely blocked the effect of nezavist. supporting the conclusion that nezavist action is through the GABA-A receptor system.PATENT

[0171] Example 4

[0172] Is nezavist action unique or would any GABA-AR PAM produce the same effect? We utilized diazepam, a classic high affinity ligand for the benzodiazepine binding site on the GABA-AR

[0105] , Diazepam acts as a PAM when it interacts with the benzodiazepine site on the GABA-AR

[0106] , FIG. 9 illustrates that application of diazepam (at what can be considered a saturating concentration for GABA-ARs) produced no significant effect on vagal afferent neuron firing patterns. What could explain the differences in response to nezavist versus diazepam? One plausible explanation is that the GABA-AR in the gut that mediates the effect of nezavist contains a 5 subunit instead of a y subunit. Diazepam cannot function in the presence of a 5 subunit

[0107] while nezavist can produce its PAM effect in the presence of either the 5 or y subunits

[0100] ,

[0173] There is ample evidence for the presence of GABA-ARs in the intestine [94, 95] however, there has been no report of GABA-A receptors being present directly on the sensory endings of the vagus neurons. There is a report that GABA-A receptors containing a 5 subunit are present on the enteroendocrine cells which secrete cholecystokinin (CCK) in the intestine

[0030] , It should be noted that activation of GABA-ARs on these CCK-releasing enteroendocrine cells leads to membrane depolarization and potentiation of CCK release

[0030] , Vagal neurons contain receptors for CCK

[0108] and thus the effects of nezavist on vagal neuron firing may be secondary to nezavist-mediated release of CCK and CCK action on the vagus. FIG. 9 illustrates that exogenous application of CCK to the jejunum produced an identical pattern of changes in vagal neuronal firing as seen with nezavist. The similarity in the actions of CCK and nezavist provide a plausible path by which nezavist can activate the firing of a subset of vagal afferent neurons. Reliable data exist to demonstrate that CCK acting at the level of the intestine and activating the vagal neurons can generate an anti-neuroinflammatory response [109-111], Irrespective of the mechanism, it is evident that nezavist can act at the level of the intestine to significantly activate vagal afferent neurons.

[0174] Example 5

[0175] Activation of a subset of afferent sensory vagal neurons innervating the gut should result in a response of second order neurons located in the NTS to which these sensory neurons project

[0112] , The effect of a drug such as nezavist on the response of the second order neurons can be positive or negative depending on the activity of the second order neuron at the time that the nezavist-determined signal arrives. A method for monitoring the response of neurons to sensory input is through measuring the expression of immediate early genes such as c-Fos

[0112] ,PATENTWe were particularly interested in whether nezavist could modulate the response to lipopolysaccharide (LPS) of the second order neurons in the vagal pathway. As noted earlier, LPS is an antigen derived from a bacterial cell wall. LPS administration is an instigator of neuroinflammation and has many times been shown [112, 113] to increase expression of c-Fos in cell bodies of neurons in the NTS that also receive vagal afferent input. FIGS. 10A-10C show that nezavist. administered i.p., reduced the LPS-induced increase in the number of c-Fos positive cells in the NTS, with a significant effect in the posterior portion of the NTS, where the cell bodies of neurons that project to the locus coeruleus (LC) are located. Cell bodies in the LC project to several brain areas, including hippocampus.

[0176] Example 6

[0177] As noted, the administration of lipopolysaccharide (LPS) produces neuroinflammation

[0114] , The demonstrations of neuroinflammation have relied on the measurement of increased levels of inflammation-inducing cytokines (particularly IL- 1 ) in brain tissue [114, 115], changes in cell morphology in brain [114. 115], and changes in behavior attendant to and indicative of neuroinflammation [54, 115, 116], We chose to examine the hippocampus because this brain area is critical for memory and cognitive function and because LPS-induced neuroinflammation has been considered a significant factor in cognitive decline and memory as animals age[3]. We chose to use the well accepted LPS-induced inflammation model [114, 115] to study the effect of nezavist on neuroinflammation and monitor the signs of neuroinflammation by ascertaining the increase in the levels of synthesis of four neuroinflammatory cytokines

[0117] in hippocampal tissue after LPS injection.

[0178] We also monitored the morphology7of microglia. The transition of microglia from the activated neuroinflammatory state (microglia Ml phenotype) to the resting, neurosurveillance (microglia M2 phenotype) and vice versa is marked by notable changes in morphology. The resting (M2) state of microglia is characterized by a small soma with multiple ramifications (cell processes), while the activated (Ml) state, which is accompanied by a substantial increase in cytokine production and phagocytosis, is characterized by an enlarged cell body and, at full activation, an amoeboid appearance with few cell processes [8, 10, 118], These morphologic changes can be observed to monitor the extent of microglial activation.

[0179] FIG. 11 illustrates the increased levels of neuroinflammatory cytokines evident in the hippocampus of mice after 4 daily treatments with LPS (0.5 mg / kg) and the selective block of this increase by daily treatments with nezavist (50 or 100 mg / kg). Both doses of nezavist significantly reduced the LPS-induced increase of hippocampal levels of IL-10, but not IL-6 orPATENTTNF-a.

[0180] In addition to the measurement of cytokines in hippocampal tissue, we examined the morphology of the microglia and their activation (Ml phenotype) in the hippocampus of the four groups of mice (vehicle / vehicle. vehicle / nezavist. LPS / vehicle, LPS / nezavist). We used an antibody for the ionized calcium-binding adaptor molecule (Iba-1) to identify and quantify activated microglia in the hippocampus of mice treated as described in FIG. 11. Iba-1 is a commonly used marker for measuring microglial activation

[0119] , FIG. 12 shows hippocampal tissue after staining for Iba-1 and the quantification of the hippocampal Iba-1 staining. A diminution in cells stained with Iba-1 (activated microglia) was noted in the LPS / nezavist groups compared to the LPS / vehicle group of mice.

[0181] The measures of c-Fos levels in NTS, and of microglial activation based on levels of pro-neuroinflammatory cytokines and microglial morphology, indicate that the LPS injection produced significant neuronal activation and neuroinflammation and that nezavist administered after LPS reduced or eliminated the cardinal signs of a neuroinflammatory response to LPS. Thus, nezavist and compounds similar in structure and function at the intestinal GABA-A receptor can activate particular vagal nerve neurons and generate signals that ameliorate neuroinflammation.

[0182] Example 7

[0183] Synthesis of CM-113 is performed with 1.0M n-Propylmagnesium chloride solution in 2-methyltetrahydroduran (0.15 mL, 0.15 mmol) was added dropwise to a solution ofWeinreb amide CM-112 (70 mg, 0. 14 mmol) in dry THF (5 mL) at -10 °C under N2. Following addition, the reaction mixture was stirred at -10 °C for 30 mm, before being allowed to warm to RT and stirred for an additional 3 hrs. TLC indicated that a significant portion of additional n- propylmagnesium chloride solution was required, and the so the process was repeated with a further 8 eq (1. 12 mL) added in 2 equivalent portions (0.28 mL) over 4 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL) and the product was extracted with EtOAc (3 x 10 mL). The organic extract was washed with brine (10 mL) and dried (MgSO4) before being evaporated to dryness. The residue w as purified via chromatography on silica (4: 1 Hexanes: EtOAc) to afford the target compound as a pale yellow- solid (20 mg, 0.04 mmol, 29%).

[0184] Synthesis of CM-113:PATENT

[0185] It is understood that the examples, embodiments, and aspects described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and scope of this application and appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference herein their entirety and for all purposes.

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Claims

PATENTCLAIMSWhat is claimed is:

1. A method of treating neuroinflammation in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor.

2. A method of stimulating a vagus nerve in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p_interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor.

3. A method of treating a neuropathology' caused by neuroinflammation in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound that is a positive allosteric modulator of GABA-A receptors, wherein the compound binds to the a+ / p- interface of GABA-A receptors and / or the etomidate site of the GABA-A receptor.

4. The method of claim 1 or 3, wherein the neuroinflammation is chronic neuroinflammation.

5. The method of claim 3 or 4, wherein the neuropathology' is a psychiatric disease.

6. The method of claim 5, wherein the psychiatric disease is depression, anxiety7, post-traumatic stress disorder, or schizophrenia.

7. The method of claim 3 or 4, wherein the neuropathology' is a neurological disease.

8. The method of claim 5, wherein the neurological disease is Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease.

9. The method of claim 3 or 4, wherein the neuropathology' is a stroke, a traumatic brain injury’, a spinal cord injury, a migraine, myalgic encephalomyelitis / chronic fatigue syndrome, or Gulf War syndrome.

10. The method of any one of claims 1 to 9, wherein the patient has an increased expression level of an inflammatory cytokine, relative to a healthy control.

11. The method of claim 10, wherein the inflammatory cytokine is TNFa, IL-6, IL-PATENT1 P, MCP-1, or a combination of two or more thereof.

12. The method of any one of claims 1 to 11, wherein the administering is peripherally administering.

13. The method of any one of claims 1 to 12, wherein the GABA-A receptors do not contain a 5 subunit or a y subunit.

14. The method of any one of claims 1 to 12, wherein the GABA-A receptors contain a 5 subunit.

15. The method of any one of claims 1 to 12, wherein the GABA-A receptors contain a y subunit.

16. The method of any one of claims 1 to 15, wherein the compound that is the positive allosteric modulator of GABA-A receptors is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:whereinR1is H, C2-C4 alkyd, C2-C4 alkenyl, halogen, ZXR9, orNCR10)^11);R2is H, C1-C4 alkyl, C2-C4 alkenyl, halogen, Z2R12, N(R13)(R14), or C1-C4 alkyl substituted with one or more moiety selected from the group consisting of C1-C4 alkyd. C2-C4 alkenyl, halogen, Z3R15, and N(R16)(R17);R3, R4, R5, and R6are each independently H, C1-C4 alkyl, C2-C4 alkenyl, halogen, -NO2, Z3R18, or N(R19)(R20);X1is N or CH;R7and R8are each independently H, Ci-Cg alkyl, C2-C4 alkenyl, C2-C4 alkynyl, aryl, or Ci-Ce alkyl substituted with one or more moiety7selected from the group consisting of C1-C4 alkyd, C2-C4 alkenyl, nitro, halogen, Z4R21, and N(R22)(R23); or R7and R8together with X1form a 5 to 8 member saturated, unsaturated, or aromatic organic cyclic or heterocyclic moiety7;R9, R10. R11, R12, R13, R14, R15. R16, R17, R18. R19, R20, R21, R22, and R23are eachPATENT independently H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more moiety selected from the group consisting of Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen, heteroaryl. Z5R24, and N(R25)(R26);Z1, Z2, Z3, Z4, and Z5are each independently -O-, -S, -NH-, -C(=O)O-, -OC(=O)-, -C(=O)-, or -C(=O)NH-; andR24, R25, and R26are each independently is C1-C4 alkyl.

17. The method of claim 16, wherein the compound of Formula (I) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:

18. The method of claim 17, wherein R1is ZXR9; R3and R5are independently H, C1-C4 alkyl, C2-C4 alkenyl, halogen, or -NO2; R7and R8are each independently Ci-Ce alkyl, C2-C4 alkenyl, C2-C4 alkynyl, or phenyl; R9is H or Ci-Ce alkyl; and Z1is -C(=O)O-, -OC(=O)-, or -C(=O)-.

19. The method of any one of claims 16 to 18, wherein R3and R5are independently halogen.

20. The method of any one of claims 16 to 19, wherein R7and R8are phenyl.

21. The method of any one of claims 16 to 20, wherein R1is ZXR9; Z1is -C(=O)- and R9is Ci-C6alkyl.

22. The method of any one of claims 16 to 20, wherein R1is Z'R9; Z1is -C(=O)O- and R9is C1-C4 alkyl.

23. The method of claim 16, wherein the compound of Formula (I) is a compound of Formula (A) or a pharmaceutically acceptable salt thereof or a compound of Formula (B) or a pharmaceutically acceptable salt thereof:PATENT24. A compound, wherein the compound is(i) a compound of Formula (A) or a pharmaceutically acceptable salt thereof:(ii) a compound of Formula (B) or a pharmaceutically acceptable salt thereof:(iii) a compound of Formula (C) or a pharmaceutically acceptable salt thereof:PATENT

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