Date of Award

August 2014

Degree Type

Thesis

Degree Name

Master of Science

Department

Chemistry

First Advisor

James M. Cook

Committee Members

Arsenio Andrew Pacheco, Alexander E. Arnold

Abstract

GABAA complexes are a class of receptors that respond to the neurotransmitter GABA, the chief inhibitory neurotransmitter in the vertebrate CNS. A widely accepted pharmacological target for enhancing cognition is the benzodiazepine-binding site on the gamma-aminobutyric acid type A (GABAA) receptor complex. Inverse agonists acting at 5 subunits containing GABAA receptors are thought to act as cognitive enhancers while eliminating unwanted side effects associated with non-selective compounds. From the recent work of Rowlett, Cook et al. it was demonstrated that the novel 5 selective inverse agonist PWZ-029 (20) was active as a cognitive enhancer in rhesus monkeys in the CANTAB paradigm. This ligand (PWZ-029) is about 60-fold more selective for the 5 subunit compared to 1, 2 and 3 GABA(A)ergic receptors. It is found that PWZ-029 significantly attenuated scopolamine-induced impairment of contextual memory in rodents and primates. In the object retrevial task, PWZ- 029 showed only a modest trend for enhancement of performance, but when task difficulty was increased by testing with difficult trials only, PWZ-029 robustly increased performance. In addition, PWZ-029 enhanced performance in the DNMS (Delayed non-matching to sample) task using the 10 minute delay with distracters. This ligand also exhibited anxiolytic activity in some primates and was an orally active anticonvulsant in rats (James Stables, NINDS). GABAA receptor complexes that contain subunits are abundantly expressed in the hippocampus and therefore considered to be a therapeutic target for treating cognitive disorders, like Alzheimer's and ADHD. In order to search for better agents, a number of analogs of PWZ-029 were prepared in this research and have been sent out for biological testing. In order to do this a key benzylic bromide was prepared and purified which is a key to future work, stability issues with this bromide were solved which is important to success in this research.

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