Clinical studies demonstrated the value of cholinergic compounds to improve cognition in patients with Alzheimer's disease, AD. The actions of cholinesterase (ChE) inhibitors compared to muscarinic agonists, administered under optimal steady-state conditions, were more robust in the same patients. However, the actions of the former were limited by dose-limiting, primarily peripheral, side effects. Potent, novel agents, phenserines, were developed that dissociated the beneficial actions of antiChE therapy in brain from its adverse brain and peripheral ones by incorporating into the agents brain and enzyme subtype (acetylcholinesterase, AChE) selectivity. The agents have demonstrated dramatic ability to improve memory performance in animal models of AD, and are the first agents to inhibit the in vivo production of the brain protein, b-amyloid precursor protein (Ab), the source of the putative toxin beta-amyloid, formed in the AD brain. The lead compound is presently undergoing FDA-approved preclinical toxicological assessment in rats and dogs to allow its rapid clinical assessment. Its toxicological profile appears to be highly favorable. Additional studies are defining novel targets and drug candidates. Specifically, these include novel nicotinic agents to modulate cognitive performance, antiviral agents of potential for AIDS-associated dementia, drugs for the treatment of cancers of the brain, breast and lymphatics, and modulators of cocaine metabolism for the treatment of drug abuse.
