Richard Alan Earl

Intramolecular [3+2] cycloadditions of functionalized azomethine ylides

Abstract The use of dithiane chemistry to synthesize functionalized azomethine ylides which are then employed in [3+2] cycloaddition chemistry is described. The advantages of this methodology as well as an approach to the lycorenine alkaloid system are presented.

Neurotransmitter Release Enhancement as a Possible Therapy for Neurodegenerative Diseases: Update on Linopirdine (DUP996)

Cholinergic approaches to palliate the symptoms of Alzheimer’s disease (AD) have focussed on the discovery and development of direct cholinergic agonists or cholinesterase inhibitors. As an alternative approach to develop drugs that bolster compromised cognitive processes, increasing presynaptic release of acetylcholine (ACh) offers another means of enhancing cholinergic activity. The aminopyridines have long been known to increase neurotransmitter release, but these compounds increase release under basal as well as stimulated conditions. Nickolson et al. (1990) hypothesized, however, that compounds which specifically enhance stimulated ACh release would prove to be superior therapeutic agents. Their efforts to identify compounds which enhance K+-stimulated and not basal release of ACh led to the discovery of linopirdine (DuP996), an agent which has undergone clinical evaluation for its efficacy in AD patients.