NI-004

This review explores the main aspects that form the basis of the cholinergic-oriented treatment of Alzheimer disease. Muscarinic acetylcholine receptor subtypes in the brain and periphery are discussed. It includes a new and updated overview of the involvement of muscarinic receptors in Alzheimer disease and the recent development of new and highly selective M1 muscarinic receptor agonists with disease-modifying potential. Activation of the M1 muscarinic receptor is a rational therapeutic strategy for the treatment of schizophrenia and Alzheimer disease, as this receptor plays a pivotal role in modulating cognitive deficits and the pathology of the disease. Such activation can be achieved through M1 allosteric and bitopic muscarinic agonists, M1 positive allosteric modulators (M1 PAMs), and direct-acting M1 muscarinic orthosteric agonists. The efficacy of M1 PAMs depends on acetylcholine, which declines in Alzheimer disease as postsynaptic neurons lose cholinergic input from the basal forebrain. On the other hand, the activity of M1 muscarinic orthosteric agonists is independent of the functional or anatomic integrity of presynaptic cholinergic terminals, and likely retain efficacy as the disease progresses, even after presynaptic degeneration of cholinergic fibers. Based on the acceptance criteria for a preferred M1 muscarinic agonist for the treatment of AD, aiming for efficacy, specificity, and safety in clinical use, few M1 muscarinic agonists fulfill these requirements, such as orthosteric M1 agonists-cevimeline (aka AF102B), the first FDA-approved M1 agonist, and NSC001 (aka AF267B). The pros and cons of various muscarinic agonists developed are critically discussed in comparison to these drugs. The review proposes new alternatives to cholinergic therapy, particularly selective M1 muscarinic drugs, that should be designed to amplify its clinical effect and supplement the disease-modifying effect of new treatments to slow down or arrest disease progression.