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. M 2 muscarinic receptor activation inhibits ACh release in brain regions that are critical for learning and memory processes. Thus, M 2 antagonists may prove beneficial for relief of cognitive deficits in AD. In this review, early discoveries of M 2 muscarinic antagonists based on dibenzodiazepinones, natural products, piperazines, and piperidines are described. More specifically, the development of a benzylidene ketal class of M 2 muscarinic antagonists is reviewed. Characterization and optimization of these agents have led to the identification of compounds with high M 2 receptor affinity and subtype selectivity. These M 2 antagonists also facilitate ACh release and enhance cognition in preclinical experimental paradigms. While clinical efficacy of these compounds has not been evaluated, M 2 antagonists represent a promising treatment for AD. Drug Dev. Res. 56:310-320, 2002.

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

“…This selectivity profile agrees with what was reported for other muscarinic derivatives bearing the diphenylsulfone moiety. 51 …”

Alzheimer's disease: Targeting the Cholinergic System

“…In addition to M1 agonists, M1 allosteric modulators have also been proposed as potential pharmacological tools to treat AD, as they can decrease Aβ production [ 249 ]. Moreover, the use of M2 antagonists, such as SCH-57790 and SC-72788, can lead to blockage of M2-mediated inhibition of presynaptic release of ACh, which can activate M1 and nicotinic receptors, ameliorating cognitive impairment in AD [ 250 ]. In addition, activation of M2 receptors can cause an increase in Aβ production [ 251 ].…”

Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer's Disease

“…This would distinguish the M2 antagonists from M1 agonists, and serves to make this treatment approach more like AChE-Is at the level of the synapse. 62 Some selective M2 antagonists, such as SCH-57790 and SC-72788, 63 restored memory impairments in animal models that mimic to some extent the cholinergic hypofunction in AD. These studies suggest that selective blockade of M2 mAChR may be a viable strategy for restoration of cognitive impairments.…”