We have sought to improve upon the activity of the well known AcCh-releasing agents, 4-aminopyridine and 3,4-diaminopyridine. This work has led to the discovery of a series of ureas with AcCh-releasing properties. From this series, compound 5 has emerged as a potent AcCh-releasing agent with promising in vivo activity. The cholinergic hypothesis of age-related dementia has provided a catalyst for exploring various means of enhancing cholinergic function. Focusing on the cholinergic synapse, one might consider new therapeutic agents that target the pre-, intra- and/or post-junctional sites. Cholinesterase inhibitors and muscarinic agonists are representative of the latter two categories. Agents that act at the pre-synaptic cholinergic neuron are much less well known and characterized. Among the best studied examples to date are the aminopyridines, which increase the release of AcCh in a variety of brain regions, owing to effects on K+ and Ca2+ ion channels. Recently a new series of AcCh releasing agents was disclosed related to DUP 996; these compounds are also claimed to induce AcCh release, though the mechanism of action remains unclear. In principle, stimulated AcCh release could provide a more natural phasic enhancement of cholinergic function than persistent tonic post-synaptic stimulation.