The GABAA receptor is a pentameric neurotransmitter gated chloride ion channel composed of five transmembrane protein subunits. Multiple cDNAs (DNA that is complementary to RNA) that encode GABAA receptor subunits have been cloned and, based on sequence homology, eight subunit families (α, β, γ, δ, ε, θ, π, ρ) comprising 20 distinct gene products have been identified (See illustration) Based on just the α, β and γ subunits, immunoprecipitation studies suggest the presence of perhaps 10 distinct hetero-pentamers, creating a considerable degree of receptor subtype heterogeneity.
Benzodiazepines (BDZ), such as Valium® (diazepam), Librium® (chlordiazepoxide) and Xanax® (alprazolam) were the first major class of drugs reported to act as GABAkines (GABAA PAMs), by binding at a site distinct from the binding site for GABA. These drugs produced a wide range of pharmacological properties, some desirable and some not, including anxiety reduction, sedation, hypnosis, anti-convulsant, muscle relaxation, respiratory depression, cognitive impairment, as well as tolerance, abuse and withdrawal. For this reason, it was not surprising that benzodiazepines were observed to act as GABA PAMs indiscriminately across all GABAA receptor subtypes. Following the identification of BDZ binding sites on GABAA receptors, Dr. Lippa described CL218,872, the first non-BDZ to demonstrate that these receptors were heterogeneous by binding selectively to a subtype of GABAA receptor. This demonstration of receptor heterogeneity led to the hypothesis that the various pharmacological actions of the BDZs might be separable. In animal testing, CL218,872 provided the proof of principle that such a separation could be achieved by displaying anti-anxiety and anti-convulsant properties in the absence of sedation and muscular incoordination. These findings gave impetus to the search for novel therapeutic drugs for neurological and psychiatric illnesses that display improvements in efficacy and reductions in side effects.
While CL218,872 was not clinically tested in humans, Dr. Lippa identified a related derivative compound, ocinaplon, which displayed similar receptor subtype selectivity and also produced the same pharmacological profile in animal studies as did CL218,872. In Phase 1 clinical studies, ocinaplon was safe and well-tolerated with no BDZ-like effects noted. In two Phase 2 clinical trials in patients suffering from chronic general anxiety disorder (GAD), ocinaplon produced a rapid, highly significant reduction in anxiety scores with no evidence of BDZ-like side effects. Development of ocinaplon was halted due to elevations in liver function tests observed in a small number of patients during the conduct of a larger Phase 3 clinical trial. Nevertheless, these results with ocinaplon greatly reinforced the hypothesis that drugs could be developed that selectively produced certain therapeutic effects of the BDZs without displaying their undesirable side effects.
Over the last several years, a group of scientists led by Drs. James Cook and Jeffrey Witkin, now Scientific Team Leaders for RespireRx, have synthesized and tested a broad series of novel chemical compounds that display GABAA receptor subtype selectivity and pharmacological specificity. As part of an option to license agreement with the University of Wisconsin (UWMRF), RespireRx intends to acquire, by September 2020, rights to certain of these chemical compounds.
Of these compounds, we have emphasized KRM-II-81as a clinical lead. KRM-II-81 is the most advanced and druggable of a series of compounds that display certain receptor subtype selective and pharmacological specificity. In studies using cell cultures, brain tissues and whole animals, KRM-II-81 acts selectively as a GABAkine at GABAA receptor subtypes that we feel are intimately involved in neuronal processes that underly epilepsy, pain, anxiety and certain other indications. KRM-II-81 has demonstrated highly desirable properties in animal models of of these indications, in the absence of or with greatly reduced liability to produce sedation, motor incoordination, cognitive impairments, respiratory depression, tolerance, abuse and withdrawal seizures, all side effects associated with benzodiazepines. We currently are focused on the potential treatment of epilepsy and pain.