New M1 Agonists: Selective Signaling, Neurotrophic-Like and Cognitive Effects — Implications in the Treatment of Alzheimer’s Disease

To date five structurally different human muscarinic acetylcholine receptor (mAChR) subtypes (ml-m5) proteins have been cloned and expressed in suitable cell systems (Bonner et al., 1987). It is likely that the ml, m2, m3, and m4 AChRs fit the pharmacological definition of the M1, M2, M3 and M4 AChRs, respectively (Buckley et al., 1989; reviewed by Hulme et al., 1990). Muscarinic receptors are members of the G-protein coupled receptor superfamily. The mAChRs have two binding domains, a ligand-binding extracellular (and including membrane-spanning) domain and a G-protein binding intracellular domain. This second domain, by interaction with various G-proteins, controls and modulates second messenger systems. It was shown that the ml, m3 and m5 AChRs are closely related in sequence and apparently are functionally almost similar. When expressed in mammalian cells, these receptor subtypes couple efficiently to phosphoinositide (PI) turnover. The m2 and m4 AChRs are less related to the ml, m3 and m5 AChRs, and when expressed in mammalian cells are efficiently coupled to the inhibition of adenylate cyclase (Bonner et al., 1987; Hulme et al., 1990).