Development of M1 subtype selective muscarinic agonists for Alzheimer's disease: Translation of in vitro selectivity into in vivo efficacy

Clinical trials in Alzheimer's disease (AD) with first generation muscarinic agonists (e.g., arecoline, oxotremorine, pilocarpine) produced inconsistent results due to poor pharmacokinetic properties and a lack of separation between central and peripheral activities observed with these compounds. Second generation agonists have sought to optimize physicochemical properties, and in most cases, target specific subtypes of muscarinic receptor to overcome these limitations. Based upon receptor distribution in both central and peripheral nervous systems, agonists of the m1/M1 subtype seem to possess the desired profile for AD treatment. For the discovery and characterization of these selective agents, the use of clonal cell lines expressing the five subtypes of muscarinic receptors (m1–m5) has become pivotal. However, their use is not without limitations. Results from functional assays (e.g., activation of second messengers) reliably measures subtype selectivity, whereas receptor binding underestimates selectivity. From a novel series of azabicyclic oximes, PD151832 has been chosen for further development and data obtained with this M1 muscarinic agonist is used to exemplify central and peripheral animal models of cholinergic activity and the ability to translate in vitro subtype selectivity into in vivo efficacy. Drug Dev. Res. 40:133–143, 1997. © 1997 Wiley-Liss, Inc.