RespireRx Pharmaceuticals Inc. announced that scientists associated with the Company have published a review article entitled “GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors” in the peer reviewed journal Pharmacology and Therapeutics (Elsevier, https://doi.org/10.1016/j.pharmthera.2021.108035). The multidisciplinary team of authors was led by Drs. James M. Cook and Jeffrey M. Witkin, both of whom are RespireRx Research Fellows and Dr. Rok Cerne, RespireRx Senior Research Scientist, in addition to their academic affiliations at University of Wisconsin-Milwaukee, Ascension St. Vincent and Indiana University/Purdue University, respectively. Authors also include Arnold Lippa, RespireRx Executive Chairman and Chief Scientific Officer, Michael M. Poe, Jodi L. Smith, Xiaoming Jin, Xingjie Ping and Lalit K. Golani. This article discusses the history, evolution and present day development of GABAkines, a term which refers to a broad class of drugs that produce their pharmacological properties by enhancing the actions of the neurotransmitter GABA, the major inhibitory neurotransmitter in the brain, at GABAA receptors. Traditional GABAkines such as the benzodiazepines (BDZ) Valium® (diazepam), Librium® (chlordiazepoxide) and Xanax® (alprazolam) have been widely used medicines for over 70 years for the treatment of anxiety, epilepsy, sleep, and other disorders. Unfortunately, because GABA is found throughout the brain and BDZ indiscriminately act upon all GABAA receptors, they also produce undesirable side effects such as sedation, motor-impairment, tolerance, dependence and abuse, which have raised concerns regarding their safety and tolerability. As a result of the prior research of Dr. Lippa identifying specific subtypes of GABAA receptors, hopes were raised regarding the possibility that different subtypes might be responsible for the different pharmacological properties produced by GABAA receptor activation. Shortly thereafter, Dr. Lippa identified novel compounds that, unlike like the broadly acting BDZ, acted upon a specific GABAA subtype and produced anti-anxiety effects in animals and humans without the attendant sedation and motor impairment common to BDZ. While clinical development of these compounds was halted due to potential liver enzyme concerns, they nevertheless encouraged considerable research and development into GABAA receptor subtype specific drugs. This article describes the current state of GABAkines undergoing development, including KRM-II-81, the Company’s lead GABAkine. KRM-II-81, originally synthesized by Dr. Cook, is being developed by the Company’s EndeavourRx business unit because of its ability to selectively amplify inhibitory neurotransmission at a highly specific, subset of GABAA receptors, thus producing a unique efficacy profile with reduced side effects. Preclinical studies have documented its efficacy in a broad array of animal models of interrelated neurological and psychiatric disorders including epilepsy, pain, anxiety, and depression in the absence of or with greatly reduced propensity to produce sedation, motor-impairment, tolerance, dependence and abuse. The Company currently is focusing on developing KRM-II-81 for the treatment of epilepsy and pain. 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. Pharmaco-resistance occurs when medications that once controlled seizures lose efficacy as a result of chronic use and it is a principle reason some epileptic patients require brain surgery to control their seizures. Not only was KRM-II-81 highly effective in treatment resistant and pharmaco-resistant models, but pharmaco-resistance did not develop to its anti-convulsant properties. These latter results are particularly important because, while BDZ are front-line treatment for seizures, their chronic use for epilepsy is limited due to the rapid development of tolerance. In support of its potential clinical efficacy, translational studies have demonstrated the ability of KRM-II-81 to dramatically reduce epileptiform electrical activity when administered in situ to brain slices excised from treatment resistant epileptic patients undergoing surgery. In addition, KRM-II-81 has displayed a high degree of analgesic activity in a broad range of preclinical studies. In cellular studies, KRM-II-81 preferentially bound to specific subtypes of GABAA receptors and boosted the ability of GABA to inhibit pain sensory neurons in the spinal dorsal root ganglia. In intact animal models of acute and chronic pain, the analgesic efficacy of KRM-II-81 was comparable to or greater than commonly used analgesics. At the same time, KRM-II-81 did not display side effects such as sedation and motor impairment, but even more importantly, it did not produce tolerance, dependence, respiratory depression or behavioral changes indicative of abuse liability, which are produced by opioid narcotics and are at the heart of the opioid epidemic.