GABAA/BzR chloride ion channels comprise the major inhibitory neurotransmitter system in the CNS. This central role carries with it a direct influence on many diseases of the CNS. Inverse agonists acting at alpha 5 subunits containing GABAA receptors are thought to act as cognitive enhancers while eliminating unwanted side effects associated with non-selective compounds. The novel alpha 5 selective inverse agonist PWZ-029 was evaluated as a cognitive enhancer in rhesus monkeys in the CANTAB paradigm. This ligand had the ability to reverse cholinergic deficits in performance induced by the antimuscarinic scopolamine under mixed trial conditions. In the ORD 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. This enhancement was reversed by administration of the alpha 5 GABA (A) subtype selective antagonist Xli-093 and this antagonism in turn was reversed by increasing the dose of PWZ-029. In addition, PWZ-029 enhanced performance in the DNMS 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. The synthesis and biological activity of this inverse agonist will be discussed in regard to drug development for treatment of age-associated memory impairment and Alzheimer's disease.

Synthesis and biological evaluation of the selective inverse agonist PWZ-029 for alpha 5 Bzr/GABA<sub>a</sub>ergic receptor subtypes: This ligand enhances cognition in rhesus monkeys

240th National Meeting (2010)

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Synthesis and biological evaluation of the selective inverse agonist PWZ-029 for alpha 5 Bzr/GABAaergic receptor subtypes: This ligand enhances cognition in rhesus monkeys

Synthesis and biological evaluation of the selective inverse agonist PWZ-029 for alpha 5 Bzr/GABA_aergic receptor subtypes: This ligand enhances cognition in rhesus monkeys