Orally active and selective benzylidene ketal M2 muscarinic receptor antagonists for the treatment of Alzheimer's disease

Abstract

Numerous studies have implicated the cholinergic system as a target for Alzheimer's disease (AD) therapy. The currently marketed drugs for treatment of AD are acetylcholinesterase inhibitors, which increase levels of the neurotransmitter acetylcholine (ACh) by blocking its metabolic degradation. However, this mechanism results in a non-selective enhancement of cholinergic activity in peripheral organs as well as brain, which could lead to detrimental side effects. Cholinergic enhancement in brain can also be achieved by blocking presynaptic release-regulating autoreceptors. M2 muscarinic receptor activation inhibits ACh release in brain regions that are critical for learning and memory processes. Thus, M2 antagonists may prove beneficial for relief of cognitive deficits in AD. In this review, early discoveries of M2 muscarinic antagonists based on dibenzodiazepinones, natural products, piperazines, and piperidines are described. More specifically, the development of a benzylidene ketal class of M2 muscarinic antagonists is reviewed. Characterization and optimization of these agents have led to the identification of compounds with high M2 receptor affinity and subtype selectivity. These M2 antagonists also facilitate ACh release and enhance cognition in preclinical experimental paradigms. While clinical efficacy of these compounds has not been evaluated, M2 antagonists represent a promising treatment for AD. © 2002 Wiley-Liss, Inc.