KRM-81 / RespireRx - LARVOL DELTA

Nonsedating anxiolytics. (PubMed, Pharmacol Biochem Behav) - "This has rekindled the interest in the GABAA-receptor (GABAAR) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam...Advances in molecular biology gave birth to a host of subtype selective GABAAR-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)...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 GABAAR for improved therapeutic gain and reduced side effects."

Journal • Review • Anesthesia • CNS Disorders • Depression • Hepatology • Mood Disorders • Psychiatry

Evaluation of the sedative-motor effects of novel GABAkine imidazodiazepines using quantitative observation techniques in rhesus monkeys. (PubMed, J Psychopharmacol) - "Quantitative behavioral observation was conducted by trained observers following administration of multiple doses of the conventional benzodiazepine alprazolam and the GABAkines MP-III-80 (preferential efficacy at α2/α3/α5GABAA subtypes), KRM-II-81, MP-III-24 (both with preferential efficacy for α2/α3GABAA subtypes), and MP-III-22 (preferential potency and efficacy for α5GABAA subtypes). GABAkines with preferential efficacy at α2/α3GABAA and/or α5GABAA subtypes engendered sedative-motor effects in monkeys, although only compounds with α5GABAA activity engendered deep sedation. Moreover, the significant relationship between potency obtained with in vitro electrophysiology data and the rest/sleep posture measure suggests a role for the α5GABAA subtype in this milder form of sedation."

Journal • Anesthesia • Ataxia • Movement Disorders

Antinociceptive effects of α2/α3-subtype selective GABAA receptor positive allosteric modulators KRM-II-81 and NS16085 in rats: behavioral specificity. (PubMed, J Pharmacol Exp Ther) - "The benzodiazepine midazolam was used as a comparator in these studies. Significance Statement This study demonstrates that α2/α3-subtype selective GABAA PAMs KRM-II-81 and NS16085 produce selective antinociceptive effects devoid of sedation, myorelaxation, cognitive impairment in two rat models of persistent pain. Unlikely classical benzodiazepines, this study supports the development of α2/α3-subtype selective GABAA PAMs as safe and novel analgesics for pain management."

Journal • Preclinical • Alzheimer's Disease • Anesthesia • Cognitive Disorders • Neuralgia • Pain

KRM-II-81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy. (PubMed, Heliyon) - "The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM-II-81, a novel α2/3 subtype preferring GABA 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."

Journal • CNS Disorders • Epilepsy • Oncology

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy. (PubMed, ACS Chem Neurosci) - "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."

Journal • Preclinical • CNS Disorders • Epilepsy

Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABA receptors, in a mouse model of Dravet syndrome. (PubMed, Front Pharmacol) - "The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1a mice. Selective activation for α2/3-GABAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Mood Disorders • Psychiatry

Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog. (PubMed, Drug Dev Res) - "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."

Journal • CNS Disorders • Epilepsy

Structural analogs of the GABAkine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[ f ]imidazole[1,5-α ] [1,4]diazepin-3-yl) oxazole) (KRM-II-81) are orally bioavailable anticonvulsants without sedation. (PubMed, J Pharmacol Exp Ther) - "Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to α1His102 compared to the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. An advanced compound, KPP-III-34, demonstrated efficacy in models of pharmacoresistant epilepsy. Molecular docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation."

Journal • Anesthesia • CNS Disorders • Epilepsy • Immunology

Hydrochloride Salt of the GABAkine KRM-II-81. (PubMed, ACS Omega) - "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."

Journal • CNS Disorders • Epilepsy • Pain

Synthesis of analogs of KRM-II-81, gamma aminobutyric acid type A (GABAA) receptor α2/α3 subtype-selective ligand, for epilepsy treatment without any adverse effects | Poster Board #3470 (ACS-Fall 2022) - "Moreover, in-vivo and in-vitro metabolic stability were improved and no adverse effects including ataxia, sedation, loss of righting response, and cytotoxicity were seen as desired. This work will be presented."

Adverse events • Anesthesia • Ataxia • CNS Disorders • Epilepsy • Movement Disorders

Synthesis, metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81 | Poster Board #3375 (ACS-Fall 2022) - "D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally despite its lack of augmented exposure. These findings of this new orally active anticonvulsant GABAkine, D5-KRM-II-81 will be presented."

PK/PD data • Anesthesia • CNS Disorders • Epilepsy • Neuralgia • Pain • Vascular Neurology

Antinociceptive effects of α /α -selective GABA receptor positive allosteric modulators on opioid-induced hyperalgesia. (PubMed, FASEB J) - "This study systematically examined the antinociceptive effects of α /α -selective GABA receptor PAMs alone and in combination with acetaminophen in an OIH rat model wherein repeated treatment with the opioid fentanyl induces mechanical hyperalgesia...Duration of actions of α /α -selective GABA receptor PAMs (KRM-II-81, NS16085, HZ-166) alone were studied, and combinations of KRM-II-81 and acetaminophen were also studied at fixed ratios (1:1, 1:3, 3:1)...Furthermore, KRM-II-81/acetaminophen combinations produced additive to supra-additive interactions depending on the drug mixture ratios. These findings support the idea that α /α -selective GABA receptor PAMs could serve as novel analgesics for treating OIH, and may interact favorably with other non-opioid analgesics."

Journal • Immunology • Neuralgia • Pain

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81. (PubMed, Biopharm Drug Dispos) - "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."

Journal • PK/PD data • CNS Disorders • Epilepsy

RespireRx Pharmaceuticals Inc. Announces Publication of a Manuscript Describing Its Newest Neuromodulator for Pharmacoresistant Epilepsy and Chronic Pain (GlobeNewswire) - "RespireRx Pharmaceuticals Inc...is pleased to announce that scientists associated with the Company have published a manuscript detailing the pharmacology of its newest asset, KRM-II81...the pharmacological profile of the preclinical compound KRM-II-81 is highlighted given the extensive and robust data package surrounding this asset...The Company currently is focusing on developing KRM-II-81 for the treatment of epilepsy and pain."

Preclinical • CNS Disorders • Epilepsy

Design, Synthesis, and Characterization of Novel Analogs of Clinically Progressing Gamma-Aminobutyric Acid Type A (GABAA) Receptor α2/α3 Subtype-selective Ligand KRM-II-81 for Treatment of Epilepsy (ACS-Sp 2022) - "Importantly, several novel analogs exhibited potent anticonvulsant activity with improved in-vivo and in-vitro stability in the absence of cytotoxicity, sedation, ataxia, and loss of righting response. This work will be presented."

Clinical • Anesthesia • Ataxia • CNS Disorders • Epilepsy • Movement Disorders

The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders. (PubMed, Pharmacol Biochem Behav) - "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...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."

Journal • Review • Anesthesia • CNS Disorders • Depression • Epilepsy • Mental Retardation • Neuralgia • Pain • Postpartum Depression • Psychiatry • Vascular Neurology

Antinociceptive effects of α 2 /α 3 -selective GABA A receptor positive allosteric modulators on opioid-induced hyperalgesia (Neuroscience 2021) - "This study systematically examined the antinociceptive effects of α 2 /α 3 -selective GABA A receptor PAMs alone and in combination with acetaminophen in an OIH rat model wherein repeated treatment with the opioid fentanyl induces mechanical hyperalgesia...Duration of actions of α 2 /α 3 -selective GABA A receptor PAMs (KRM-II-81, NS16085, HZ-166) alone were studied, and combinations of KRM-II-81 and acetaminophen were also studied at fixed ratios (1:1, 1:3, 3:1)...Furthermore, KRM-II-81/acetaminophen combinations produced additive to supra-additive interactions depending on the drug mixture ratios. These findings support the idea that α 2 /α 3 -selective GABA A receptor PAMs could serve as novel analgesics for treating OIH, and may interact favorably with other non-opioid analgesics.; Grant Support: NIH Grant DA047967"

CNS Disorders • Neuralgia • Pain

RespireRx Pharmaceuticals Inc. Announces Publication of Review Article Describing Advances in the Discovery, Development and Commercialization of GABAkines, Including KRM-II-81 (GlobeNewswire) - "This article describes the current state of GABAkines undergoing development, including KRM-II-81, the Company’s lead GABAkine...As described in the article, KRM-II-81 has displayed a high degree of anti-convulsant activity in a broad range of preclinical studies, including in treatment resistant and pharmaco-resistant models. Treatment resistant models are used to predict efficacy in difficult to treat forms of epilepsy."

Review • CNS Disorders • Epilepsy

GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABA receptors. (PubMed, Pharmacol Ther) - "Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence...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)...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 receptor potentiation for therapeutic gain in neurology and psychiatry."

Journal • Review • Anesthesia • CNS Disorders • Depression • Epilepsy • Mood Disorders • Movement Disorders • Pain • Postpartum Depression • Psychiatry

RespireRx Pharmaceuticals Inc. Provides Update on Its Development Programs (GlobeNewswire) - "Preclinical studies have documented its efficacy in a broad array of animal models of inter-related neurological and psychiatric disorders including epilepsy, chronic pain...KRM-II-81 is the latest GABAkine to begin development in IND-enabling toxicology investigations as a joint program of RespireRx and the University of Wisconsin-Milwaukee....'We are excited about the prospect that this novel GABAkine may give hope to those patients burdened with intractable epilepsy or chronic pain.'"

Preclinical • CNS Disorders • Epilepsy • Pain