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Positive allosteric modulators of GABA A receptors transduce a host of beneficial effects including anxiolytic actions. We have recently shown that bioavailability and anxiolytic-like activity can be improved by eliminating the ester functionality in imidazo[1,5- a ][1,4]diazepines. In the present series of experiments, we further substantiate the value of heterocyle replacement of the ester for potential treatment of anxiety. None of three esters was active in a Vogel conflict test in rats that detects anxiolytic drugs like diazepam. Compounds 7 and 8 , ester bioisosters, were selective for alpha 2 and 3 over alpha 1-containing GABA A receptors but also had modest efficacy at GABAA alpha 5-containing receptors. Compound 7 was efficacious and potent in this anxiolytic-detecting assay without affecting non-punished responding. The efficacies of the esters and of compound 7 were predicted from their efficacies as anticonvulsants against the GABA A antagonist pentylenetetrazole (PTZ). In contrast, the related structural analog, compound 8 , did not produce anxiolytic-like effects in rats despite anticonvulsant efficacy. These data thus support the following conclusions: 1) ancillary pharmacological actions of compound 8 might be responsible for its lack of anxiolytic-like efficacy despite its efficacy as an anticonvulsant 2) esters of imidazo[1,5- a ][1,4]diazepines do not demonstrate anxiolytic-like effects in rats due to their low bioavailability and 3) replacement of the ester function with suitable heterocycles markedly improves bioavailability and engenders molecules with the opportunity to have potent and efficacious effects in vivo that correspond to human anxiolytic actions. [ABSTRACT FROM AUTHOR]

Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of α2/3-containing GABA A receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of α2/3-selective PAMs has been presented along with the clinical potential for a milder motor-impacting profile compared to non-selective GABA A receptor PAMs. A new series of α2/3-selective PAMs was recently introduced which has anxiolytic and anticonvulsant activity in rodent models. These molecules also produce efficacy against pain in multiple animal models. Additionally, co-morbid states of depression are prevalent among patients with pain and patients with anxiety. Compounds were shown to be selective for α2 and α3 constructs over α1 (except KRM-II-82), α4, α5, and α6 proteins in electrophysiological assays in transfected HEK-293T cells. Utilizing the forced-swim assay in mice that detects conventional and novel antidepressant drugs, we demonstrate for the first time that α2/3-selective PAMs are active in the forced-swim assay at anxiolytic-producing doses. In contrast, activity in a related model, the tail-suspension test, was not observed. Diazepam was not active in the forced-swim assay when given alone but produced an antidepressant-like effect in mice when given in conjunction with the α1-preferring antagonist, β-CCT, that attenuated the motor-impairing effects of diazepam. We conclude that these α2/3-selective PAMs deserve further scrutiny for their potential treatment of major depressive disorder. If effective, such a mechanism could add a beneficial antidepressant component to the anxiolytic, analgesic, and anticonvulsant spectrum of effects of these compounds. [ABSTRACT FROM AUTHOR]

Ampakines are a class of compounds that are positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and enhance glutamatergic neurotransmission. Glutamatergic synaptic transmission and AMPA receptor activation are fundamentally important to the genesis and propagation of the neural impulses driving breathing, including respiratory motoneuron depolarization. Ampakines therefore have the potential to modulate the neural control of breathing. In this paper, we describe the influence of ampakines on respiratory motor output in health and disease. We dissect the molecular mechanisms underlying ampakine action, delineate the diverse targets of ampakines along the respiratory neuraxis, survey the spectrum of respiratory disorders in which ampakines have been tested, and culminate with an examination of how ampakines modulate respiratory function after spinal cord injury. Collectively, the studies reviewed here indicate that ampakines may be a useful adjunctive strategy to pair with conventional respiratory rehabilitation approaches in conditions with impaired neural activation of the respiratory muscles., Competing Interests: Declaration of competing interest Sabhya Rana reports financial support and article publishing charges were provided by National Institutes of Health. David D. Fuller reports financial support was provided by National Institutes of Health. Arnold Lippa reports a relationship with RespireRx that includes: board membership, employment, and equity or stocks. Daniel P Radin reports a relationship with RespireRx that includes: employment. Jeffrey M. Witkin reports a relationship with RespireRx that includes: employment. Rok Cerne reports a relationship with RespireRx that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Anxiety disorders are the most prevalent psychiatric pathology with substantial cost to society, but the existing treatments are often inadequate. This has rekindled the interest in the GABA A -receptor (GABA A R) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam. While the GABA A R PAMs possess remarkable anxiolytic efficacy, they have fallen out of favor due to a host of adverse effects including sedation, motor impairment, addictive potential and tolerance development. A substantial effort was thus devoted to the design of GABA A R PAMs as anxiolytics with reduced sedative liabilities. Several non-benzodiazepine (BZD) GABA A PAMs progressed to clinical trials (bretazenil, abecarnil, alpidem, and ocinaplon) with alpidem obtaining regulatory approval as anxiolytic, but later withdrawn from market due to hepatotoxicity. Advances in molecular biology gave birth to a host of subtype selective GABA A R-PAMs which suffered from signs of sedation and motor impairment and only three compounds progressed to proof-of-concept studies (TPA-023, AZD7325 and PF-06372865). TPA-023 was terminated due to toxicity in preclinical species while AZD7325 and PF-06372865 did not achieve efficacy endpoints in patients. We highlight a new compound, KRM-II-81, that is an imidazodiazepine selective for GABA A R containing α2/3 and β3 proteins. In preclinical studies KRM-II-81 produced anxiolytic-like effects but with minimal sedation, respiratory depression, and abuse liability. Thus, KRM-II-81 is a newly discovered, non- BZD anxiolytic compound, which targets a selective population of GABA A R for improved therapeutic gain and reduced side effects., Competing Interests: Declaration of competing interest Authors report no conflict of interest with the exception that Rok Cerne and Arnold Lippa are associated with RespireRx Pharmaceuticals Inc. that has licensed KRM-II-81 for development., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) has reached epidemic proportions worldwide. The consequences of TBI can be severe even with repetitive mild trauma. If death and coma are avoided, the consequences of TBI in the long term typically involve dizziness, sleep disturbances, headache, seizures, cognitive impairment, focal deficits, depression, and anxiety. The severity of brain injury is a significant predictor of outcome. However, the heterogenous nature of the injury makes prognosis difficult. The present review of the literature focuses on the genetics of TBI including genome wide (GWAS) data and candidate gene associations, among them brain-derived neurotrophic factor (BDNF) with TBI and development of post-traumatic epilepsy (PTE). Molecular biomarkers of TBI are also discussed with a focus on proteins and the inflammatory protein IL1-β. The secondary medical sequela to TBI of cognitive impairment, PTE, headache and risk for neurodegenerative disorders is also discussed. This overview of TBI concludes with a review and discussion of the medical management of TBI and the medicines used for and being developed at the preclinical and clinical stages for the treatment of TBI and its host of life-debilitating symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lipsky, Witkin, Shafique, Smith, Cerne and Marini.)

Spinal cord injury (SCI) afflicts millions of individuals globally. There are few therapies available to patients. Ascending and descending excitatory glutamatergic neural circuits in the central nervous system are disrupted by SCI, making α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) a potential therapeutic drug target. Emerging research in preclinical models highlights the involvement of AMPARs in vital processes following SCI including breathing, pain, inflammation, bladder control, and motor function. However, there are no clinical trial data reported in this patient population to date. No work on the role of AMPA receptors in sexual dysfunction after SCI has been disclosed. Compounds with selective antagonist and potentiating effects on AMPA receptors have benefit in animal models of SCI, with antagonists generally showing protective effects early after injury and potentiators (ampakines) producing improved breathing and bladder function. The role of AMPARs in pathophysiology and recovery after SCI depends upon the time post injury, and the timing of AMPAR augmentation or antagonism. The roles of inflammation, synaptic plasticity, sensitization, neurotrophic factors, and neuroprotection are considered in this context. The data summarized and discussed in this paper document proof of principle and strongly encourage additional studies on AMPARs as novel gateways to therapeutic benefit for patients suffering from SCI. The availability of both AMPAR antagonists such as perampanel and AMPAR allosteric modulators (i.e., ampakines) such as CX1739, that have been safely administered to humans, provides an expedited means of clinical inquiry for possible therapeutic advances., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [AL, JMW, and RC are associated with RespireRx Pharmaceuticals Inc that owns the AMPA receptor potentiators, CX1739and CX717 discussed in this paper]., (Copyright © 2024 Elsevier Inc. All rights reserved.)

AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low-impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low-impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2-part study. Part A was a single dose escalation study (100-1200 mg, 48 patients) and Part B was a multiple dose ascending study (300-600 mg BID for 7-10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half-life of CX1739 was 6-9 hours, and T max  was 1-5 hours. CX1739 C max and AUC were dose-proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies., (© 2024, The American College of Clinical Pharmacology.)

Aim: AMPA-glutamate receptor (AMPAR) dysfunction mediates multiple neurological/neuropsychiatric disorders. Ampakines bind AMPARs and allosterically enhance glutamate-elicited currents. This report describes the activity of the water-soluble ampakine CX1942 prodrug and the active moiety CX1763. Results: CX1763 and CX1942 enhance synaptic transmission in hippocampi of rats. CX1763 increases attention in the 5CSRTT in rats and reduces amphetamine-induced hyperactivity in mice. CX1942 potently reverses opioid-induced respiratory depression in rats. CX1942/CX1763 was effective at 2.5-10 mg/kg. CX1763 lacked epileptogenicity up to 1500 mg/kg in rats. Conclusion: These data document that CX1942 and CX1763 are active and without prominent side effects in multiple pre-clinical assays. CX1942 could serve as a prodrug for CX1763 with the advantage of high water solubility as in an intravenous formulation.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulators (AMPAkines) have a multitude of promising therapeutic properties. The pharmaceutical development of high impact AMPAkines has, however, been limited by the appearance of calcium-dependent neuronal toxicity and convulsions in vivo. Such toxicity is not observed at exceptionally high concentrations of low impact AMPAkines. Because most AMPAR are somewhat impermeable to calcium, the current study sought to examine the extent to which different mechanisms contribute to the rise in intracellular calcium in the presence of high impact ampakines. In the presence of AMPA alone, cytosolic calcium elevation is shown to be sodium-dependent. In the presence of high impact AMPAkines such as cyclothiazide (CTZ) or CX614, however, AMPAR potentiation also activates an additional mechanism that induces calcium release from endoplasmic reticular (ER) stores. The pathway that connects AMPAR to the ER system involves a Gq-protein, phospholipase C β -mediated inositol triphosphate (InsP3) formation, and ultimately stimulation of InsP3-receptors located on the ER. The same linkage was not observed using high concentrations of the low impact AMPAkines, CX516 (Ampalex), and CX717. We also demonstrate that CX614 produces neuronal hyper-excitability at therapeutic doses, whereas the newer generation low impact AMPAkine CX1739 is safe at exceedingly high doses. Although earlier studies have demonstrated a functional linkage between AMPAR and G-proteins, this report demonstrates that in the presence of high impact AMPAkines, AMPAR also couple to a Gq-protein, which triggers a secondary calcium release from the ER and provides insight into the disparate actions of high and low impact AMPAkines., (© 2024 Wiley Periodicals LLC.)

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). ( S )-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, ( R )-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of ( R )-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than ( S )-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of ( R )-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with ( R )-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.

Patients with epilepsy require improved medications. Purinergic receptors were identified as late as 1976 and are slowly emerging as potential drug targets for the discovery of antiseizure medications. While compounds interacting with these receptors have been approved for use as medicines (e.g., gefapixant for cough) and continue to be explored for a number of diseases (e.g., pain, cancer), there have been no purinergic receptor antagonists that have been advanced for epilepsy. There are very few studies on the channel conducting receptors, P2X3 and P2X4, that suggest their possible role in seizure generation or control. However, the limited data available provides some compelling reasons to believe that they could be valuable antiseizure medication drug targets. The data implicating P2X3 and P2X4 receptors in epilepsy includes the role played by ATP in neuronal excitability and seizures, receptor localization, increased receptor expression in epileptic brain, the involvement of these receptors in seizure-associated inflammation, crosstalk between these purinergic receptors and neuronal processes involved in seizures (GABAergic and glutamatergic neurotransmission), and the significant attenuation of seizures and seizure-like activity with P2X receptor blockade. The discovery of new and selective antagonists for P2X3 and P2X4 receptors is ongoing, armed with new structural data to guide rational design. The availability of safe, brain-penetrant compounds will likely encourage the clinical exploration of epilepsy as a disease entity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABA A receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

KRM-II-81 (1) is an imidazodiazepine GABA A receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a K i of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 μM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1β3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM-II-81, a novel α2/3 subtype preferring GABA A receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM-II-81 might reduce seizure burden in pharmacoresistant patients., Competing Interests: James Cook is a patent holder for KRM–II–81. Arnold Lippa, Rok Cerne, and Jeffrey Witkin are associated with RespireRx Pharmaceuticals Inc that holds the license agreement for KRM–II–81., (© 2023 The Authors.)

Oxide-dispersion-strengthened (ODS) alloys have long been considered for high temperature turbine, spacecraft, and nuclear reactor components due to their high temperature strength and radiation resistance. Conventional synthesis approaches of ODS alloys involve ball milling of powders and consolidation. In this work, a process-synergistic approach is used to introduce oxide particles during laser powder bed fusion (LPBF). Chromium (III) oxide (Cr 2 O 3 ) powders are blended with a cobalt-based alloy, Mar-M 509, and exposed to laser irradiation, resulting in reduction-oxidation reactions involving metal (Ta, Ti, Zr) ions from the metal matrix to form mixed oxides of increased thermodynamic stability. A microstructure analysis indicates the formation of nanoscale spherical mixed oxide particles as well as large agglomerates with internal cracks. Chemical analyses confirm the presence of Ta, Ti, and Zr in agglomerated oxides, but primarily Zr in the nanoscale oxides. Mechanical testing reveals that agglomerate particle cracking is detrimental to tensile ductility compared to the base alloy, suggesting the need for improved processing methods to break up oxide particle clusters and promote their uniform dispersion during laser exposure.

A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5-KRM-II-81) was made as a potential backup compound and studied here in comparison to KRM-II-81. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5-KRM-II-81 had a slightly longer duration of action against clonic and tonic seizures than KRM-II-81. Oral administration of 100 mg/kg of either KRM-II-81 or D5-KRM-II-81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5-KRM-II-81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function., (© 2023 Wiley Periodicals LLC.)

To provide back-up compounds to support the development of the GABA A receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPP-III-51 did not. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposures relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain area under the curve (AUC) exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice, and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to α 1His102 compared with the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects. SIGNIFICANCE STATEMENT: A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4 H -benzo[ f ]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABA A receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1 H NMR and 13 C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Tinnitus is a highly prevalent and disabling disorder in which sound is perceived in the absence of an external auditory energy source. The disorder is complex and can arise from multiple etiologies. Co-morbid symptoms of anxiety, depression, and sleep loss are prevalent. There are no approved medications and the treatments that have been studied produce marginal improvements in symptoms. A major hypothesis of the etiology and maintenance of tinnitus is that inhibitory input mechanisms become compromised where impaired γ-aminobutyric acid (GABA) synaptic transmission has been implicated. This general idea lends support to the potential for enhanced inhibition by drugs that enhance GABA function (GABAkines) to dampen symptoms of tinnitus. Convergent evidence from neurochemical, anatomical, physiological, and pharmacological studies support the GABA A hypothesis. Although there is surprising a relatively sparse data set, examples of therapeutic efficacy have been reported with GABAkines. These studies have relied primarily on classical benzodiazepine anxiolytics like alprazolam and clonazepam. However, the possibility that novel GABAkines with unique activities might be effective have yet to be intensively explored. For example, data implicating extrasynaptic GABA A receptors in the control of tinnitus suggests the potential for extrasynaptic GABA A receptor modulators. The large medical need, a basis for further testing of the GABA A hypothesis, and the recent reinvigoration of the drug development pipeline of new GABAkines, combine to give impetus and promise for further inquiry., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Positive allosteric modulators of γ-aminobutyric acid-A (GABA A ) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABA A receptor potentiation for therapeutic gain in neurology and psychiatry., Competing Interests: Declaration of Competing Interest James Cook and Michael Poe are named as inventors on patents describing KRM-II-81 and analogs, certain rights to which have been licensed to RespireRx Pharmaceuticals Inc. Rok Cerne, Michael Poe, James Cook, and Jeffrey Witkin are members of the research advisory group for RespireRx Pharmaceuticals Inc. and Arnold Lippa serves as Executive Chairman and Chief Scientific Officer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The imidazodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo [f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a new α2/3-selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half-life of KRM-II-81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM-II-81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5-KRM-II-81) that could be evaluated as a potentially longer-acting analog. In contrast to computer predictions, peak plasma concentrations of D5-KRM-II-81 in rats were not significantly greater than those produced by KRM-II-81 after oral administration. Furthermore, brain disposition of KRM-II-81 was higher than that of D5-KRM-II-81. The half-life of the two compounds in either plasma or brain did not statistically differ from one another but the t max for D5-KRM-II-81 occurred slightly earlier than for KRM-II-81. Non-metabolic considerations might be relevant to the lack of increases in exposure by D5-KRM-II-81. Alternative sites of metabolism on KRM-II-81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5-KRM-II-81., (© 2022 John Wiley & Sons Ltd.)

GABAkines, or positive allosteric modulators of γ-aminobutyric acid-A (GABA A ) receptors, are used for the treatment of anxiety, epilepsy, sleep, and other disorders. The search for improved GABAkines, with reduced safety liabilities (e.g., dependence) or side-effect profiles (e.g., sedation) constituted multiple discovery and development campaigns that involved a multitude of strategies over the past century. Due to the general lack of success in the development of new GABAkines, there had been a decades-long draught in bringing new GABAkines to market. Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry. Herein, we also discuss possible conditions that have enabled the transition to a new age of GABAkines. We highlight the pharmacology of KRM-II-81 that has the most preclinical data reported. KRM-II-81 is the lead compound in a new series of orally bioavailable imidazodiazepines entering IND-enabling safety studies. KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([ 3 H]-TCP binding) (r = 0.71, p < 0.05) but not to σ1 receptors ([ 3 H]-SKF 10047 binding) (r = -0.31, p = 0.46) or to σ2 receptors ([ 3 H]-DTG binding) (p = -0.38, p = 0.36). This is the first report demonstrating that these dextromethorphan analogs are functional NMDA receptor antagonists in vivo. Given their potential therapeutic utility and favorable side-effect profiles, such low affinity NMDA receptor antagonists could be considered for further development in neurological (e.g., anticonvulsant) and psychiatric (e.g., antidepressant) disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)