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The presynaptic cholinergic deficits in Alzheimer’s disease (AD) indicate that a cholinergic replacement therapy might be beneficial in alleviating some of the cognitive dysfunctions in this disorder (Bartus, 1989). However, clinical trials with some muscarinic agonists (e.g. arecoline, oxotremorine, RS86, pilocarpine and bethanechol) ranked from modest improvement to lack of beneficial effects (Potter, 1987; Moos and Hershenson, 1989). It is thus important to understand the drawbacks of the tested muscarinic agonists in order to be able to design better drugs. Molecular genetics studies have revealed the existence of five distinct muscarinic receptors (mAChRs) subtypes (m1-m5; Bonner’s nomenclature) in human and rat brain (Buckley et al., 1989). It is likely that the ml and m4 AChRs fit the pharmacological definition of the M1 AChR, whereas the m2 and m3 AChRs fit the pharmacological definition of the M2 and M3 AChR’s, respectively (Buckley et al., 1989). A loss of presynaptic M2 AChRs was reported in several AD studies. In contrast postsynaptic Ml mAChRs, facilitating cellular excitation, were relatively unchanged (reviewed by Giacobini, 1990). Most of the potent muscarinic agonists, including those which were evaluated in AD patients, show adverse central and peripheral side-effects, and are either non-selective or M2>M1 selective. Thus, they may also activate inhibitory M2 autoreceptors resulting in decreased acetylcholine (ACh) release (reviewed by Potter, 1987). |
