Efficacy of GABAA a5 receptor inverse agonists in learning impaired rats

DESCRIPTION (provided by applicant): The number of patients in the United States afflicted with learning and memory disorders is rapidly increasing. This necessitates the development of new, better acting and safer medications for enhancing cognition. In this SBIR Phase I project, PhysioGenix will determine the efficacy, pharmacokinetics (PK), maximum tolerated dose and potential side-effects of PWZ-029, a benzodiazepine (BZ) compound that may prove useful for treating patients with learning and memory disorders. BZs are listed as a Core Medicine in the WHO Essential Drug List and those on the market, such as Valium and Xanax, are widely used for the treatment of anxiety, panic attacks, insomnia, agitation and seizures. BZs can cause depressing (agonist) or stimulating (inverse agonist) effects on the central nervous system by modulating the GABAA receptor, the most prevalent inhibitory receptor within the brain. However, side-effects are common in patients treated with BZs and this can limit their use. For example, Valium is a full agonist of the GABAA receptor but has a side-effect profile in patients that includes sedation, amnesia and ataxia. Nonselective BZ inverse agonists, like DMCM, are often anxiogenic and can cause seizures in animals. Because these unwanted side-effects can be attributed to nonspecific interactions of the BZs for different subunits of the GABAA receptor complex, functionally specific BZs that retain only the desired pharmacological response are being developed. GABAA receptor complexes that contain 15 subunits are abundantly expressed in the hippocampus and therefore considered to be a therapeutic target for treating cognitive disorders, like Alzheimer's and ADHD. With this in mind, PWZ-029 was designed by Dr. James Cook of the University of Wisconsin-Milwaukee, to be an inverse agonist for the GABAA receptor having subtype and functional selectivity predominantly at the 15 subunit. Recent in vitro studies in oocytes have shown that PWZ-029 has up to 60-fold more functional selectivity for the 15 subunit compared to 11, 12 and 13. Behavior tests also suggest that PWZ-029 has cognition enhancing capabilities, thereby making it a feasible therapeutic candidate. Here, the ability of PWZ-029 to enhance cognition will be assessed in both rodents and rhesus monkeys. For rodent studies, the PK of PWZ-029 will be measured in blood and brain following oral administration to assess its bioavailability. Maximum tolerated dose studies will be carried out as part of lead optimization toxicology, which may also detect if PWZ-029 will cause seizures. The proconvulsant liability of PWZ-029 will be measured directly using the PTZ mouse model. The behavior tests will incorporate rat strains that have natural deficits in cognition along with a standard scopolamine amnesia model. Finally, rhesus monkey will be used to measure potential sedative side-effects along with confirming preliminary data for the ability of PWZ-02 to enhance cognition. Success will lead to Phase II studies that will aim to expand preclinical safety and efficacy testing ultimately leading to clinical trials. Commercialization opportunities will be realized via drug development efforts for treating mental health disorders. PUBLIC HEALTH RELEVANCE: Preclinical studies that determine the bioavailability and safety of functionally selective benzodiazepine compounds, like PWZ-029, are required prior to further drug development. Screening of compounds with relevant disease models will help to assess their therapeutic potential. Patients with learning disorders and those suffering from complications due to neurodegenerative diseases will greatly benefit as PWZ-029 moves another step closer to the clinic.