DEVELOPMENT OF M-1 SUBTYPE-SELECTIVE MUSCARINIC AGONISTS FOR ALZHEIMERS-DISEASE - TRANSLATION OF IN-VITRO SELECTIVITY INTO IN-VIVO EFFICACY

Clinical trials in Alzheimer's disease (AD) with first generation musc arinic 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 p hysicochemical properties, and in most cases, target specific subtypes of muscarinic receptor to overcome these limitations. Based upon rece ptor distribution in both central and peripheral nervous systems, agon ists of the m1/M-1 subtype seem to possess the desired profile for AD treatment. For the discovery and characterization of these selective a gents, the use of clonal cell lines expressing the five subtypes of mu scarinic receptors (m1-m5) has become pivotal. However, their use is n ot without limitations. Results from functional assays (e.g., activati on of second messengers) reliably measures subtype selectivity, wherea s receptor binding underestimates selectivity. From a novel series of azabicyclic oximes, PD151832 has been chosen for further development a nd data obtained with this M-1 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 efficac y.