M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease

Abstract

M1-type muscarinic receptors (mAChR) have an important role in cognitive processing and are relatively unchanged in Alzheimer's disease (AD). Therefore, M1 agonists represent a rational treatment strategy of AD. However, some muscarinic agonists showed disappointing results in Phase III studies in AD patients. These agonists lacked M1 selectivity in vivo and/or had several major clinical limitations, precluding a proper testing of the clinical concept. There is now justified hope that selective M1 agonists could provide limited causal therapy in AD. Thus, a relation between the formation of β-amyloid peptide and amyloid plaques, tau phosphorylation, and loss of cholinergic function in AD brains has been reported. This may shift the interest in such compounds from a mere symptomatic treatment toward their use in the future as disease-modifying agents via muscarinic regulation of β-amyloid metabolism and tau phosphorylation. Such characteristics can be detected in the functionally selective M1 agonists from the AF series (e.g. AF102B, AF150(S), AF267B). These M1 agonists, inter alia, restore cognitive impairments in several animal models for AD, promote the neurotrophic and nonamyloidogenic amyloid precursor protein (APPs) processing pathways, and decrease tau protein phosphorylation. Apolipoprotein E-deficient mice have memory deficits, synaptic loss of basal forebrain cholinergic projections, and hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau. These impairments are restored by subchronic treatment with AF150(S). Furthermore, prolonged administration of AF150(S) restored cognitive and behavioral impairments in aged microcebes, an animal model that mimics AD pathology. Except M1 agonists, there are no reports on compounds having combined effects, e.g., amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable, yet unexplored, or even ignored, clinical value of such drugs. Finally, EVOXAC(TM) (Cevimeline, AF102B) was recently approved by the FDA for the treatment of dry mouth in Sjogren syndrome, an autoimmune disease that affects exocrine glands. (C) 2000 Wiley-Liss, Inc.