Ishai Karton

Rigid analogs of acetylcholine can be m1-selective agonists: implications for a rational treatment strategy in Alzheimer's disease

Abstract Rigid analogs of acetylcholine offer an opportunity for selective actions at muscarinic receptor subtypes, since restricted conformational mobility alters the capacity of ligands to adapt to subtle differences in receptor structure. AF102B , a highly rigid analog of acetylcholine, is a centrally active M1 agonist and is evaluated in light of some currently available therapeutic strategies in Alzheimers disease.

AF102B: A Novel M1 Agonist as a Rational Treatment Strategy in Alzheimer’s Disease

Alzheimer’s disease (AD), a progressive cerebral neurodegenerative disorder with no effective treatment as yet, is known to affect 5–7% of the population over age 65. This disorder is characterized by a progressive deterioration of cognitive and mnemonic abilities. Morphological, neurochemical and behavioral studies indicate a major degeneration of the central cholinergic.system in AD (1, 2). There is also evidence that noradrenergic, serotonergic, and somatostatin-like immunoreactivity are abnormal in AD, though to a lesser extent (for reviews see refs. 3 and 4). The contribution of the cholinergic dysfunction to the cognitive symptoms in AD is indicated by a direct correlation between loss of presynaptic cholinergic markers and mental test scores (1, 2). Postmortem evaluations of brains from patients with AD have revealed a select degeneration of cholinergic cells in the basal forebrain which project to the cerebral cortex and hippocampus (reviews 1–3). This degeneration is associated with a marked reduction of presynaptic cholinergic indices in these brain regions involved in cognitive processes (5). Somewhat conflicting results were reported regarding muscarinic receptors in AD. A loss of M2 muscarinic receptors was reported in a few studies (6–8 but see also 9, 10) while postsynaptic muscarinic receptors are relatively unchanged (6–9), decreased (10) or even upregulated (11).

New Muscarinic Agonists with Special Emphasis on AF102B

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).