The acetylcholinesterase inhibitors were developed in response to the observation that a severe loss of cholinergic pathways is a consistent finding in patients with Alzheimer disease. These agents are effective in many patients, particularly those in early stages of Alzheimer disease. However, because they rely on intact cholinergic nerve terminals, which continue to degenerate as the disease progresses, acetylcholinesterase inhibitors become less effective over time. In addition, acetylcholinesterase inhibitors are incapable of providing receptor selectivity—an inability that is problematic because research has shown that stimulation of M1 receptors, but not M2 receptors, is beneficial in decreasing levels of β-amyloid.
10-11
Direct-acting muscarinic agonists exert their effects postsynaptically, requiring no cholinergic terminals. Thus, these agonists should be effective much longer than acetylcholinesterase inhibitors. Muscarinic agonists may also slow the progression of Alzheimer disease by decreasing β-amyloid accumulation.
The M1 muscarinic receptor subtype represents an important therapeutic target, because it is abundant in the hippocampus and cerebral cortex, the brain regions where the cholinergic deficit is most pronounced in Alzheimer disease. This receptor subtype is involved in short-term memory.
12 Furthermore, stimulation of M1 muscarinic receptors decreases production of β-amyloid by activation of α-secretase.
13-15
The muscarinic agonist AF267B (NGX267; Torrey Pines Pharmaceutical Inc, Del Mar, California) decreased levels of β-amyloid and prevented its accumulation following lesion of cholinergic neurons in rabbits. It also decreased β-amyloid levels in a mouse model of Alzheimer disease.
16-18 Long-term treatment with the selective M1 agonists cevimeline hydrochloride (AF102B) and talsaclidine decreased β-amyloid levels in cerebral spinal fluid (CSF) of patients with Alzheimer disease.
13,19 Conversely, use of cholinergic antagonists in patients with Parkinson disease increased CSF levels of β-amyloid,
20 and M1 receptor knockout in amyloid precursor protein (APP)-transgenic mice also increased β-amyloid deposition.
21 These results indicate that treatments that increase cholinergic function may slow progression of Alzheimer disease by decreasing β-amyloid accumulation.
The M1/M4 agonist xanomeline improved cognition and decreased behavioral disturbances in patients with Alzheimer disease, but adverse gastrointestinal effects limited its use.
22,23 Xanomeline is currently being tested for its usefulness in treating individuals with schizophrenia.
24 Unfortunately, stimulation of M4 receptors by xanomeline might mitigate the drug's beneficial effects on β-amyloid.
11 Nevertheless, a combination of xanomeline and tacrine hydrochloride (the first of the acetylcholinesterase inhibitors to be clincially used for Alzheimer disease) is now being tested.
25
The orthostatic agonist AF267B is more selective for M1 receptors than is xano-meline.
10,26 It was originally tested in patients with Alzheimer disease, but it caused excessive salivation. As a result, it has since gone through phase 1 and phase 2 clinical trials for treatment of patients with xerostomia.
27
▪
Allosteric M1 Agonists—Many G protein–coupled receptors contain allosteric binding sites that are separate from the orthostatic binding site for the neurotransmitter.
28 The orthostatic muscarinic binding site is highly conserved, making development of agonists with strong receptor selectivity difficult.
28,29 For this reason, a number of newer agents have been developed to target the allosteric sites associated with M1 receptors.
30,31
Allosteric sites might differ more between different receptor subtypes than do orthorstatic sites, allowing for the development of highly specific drugs. Stimulation of an allosteric site may enhance the binding of an agonist, or it may have distinct actions of its own to increase signal transduction. Issues that need to be clarified with allosteric M1 agonists include the degree to which they are orally available and the effect of their interaction with the allosteric receptor. Allosteric M1 agonists that have been developed and tested in animal tests or clinical trials include AC-42 (4-
n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine; Acadia Pharmaceuticals Inc, San Diego, California) and its analogue 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl) propyl]-3,4-dihydro-2(1
H)-quinolone; GlaxoSmithKline, Brentford, England),
30 as well as AC-260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one; Acadia Pharmaceuticals Inc),
32 TBPB (1-(1′2-meth ylbenzyl)-1,4′-bipiperidin-4-yl)-1
H-benzo[
d]imidazol-2(3H)-one; Merck & Co Inc, Whitehouse Station, New Jersey),
33,34 and BCQA (benzylquinoline carboxylic acid; Merck & Co Inc).
35
The allosteric agonists AC-42 and 77-LH-28-1 have similar activity in vitro, but 77-LH-28-1 has been shown to have better penetration into the CNS and to stimulate rat hippocampal activity.
33 Also, AC-260584 has been shown to increase cognitive performance in an animal model,
32 but this compound has not yet been tested in humans.
The allosteric agonist TBPB is active in vivo, it is highly selective for M1 receptors,
34 and it does not appear to cause serious peripheral adverse effects, which are often mediated by M3 receptors.
27 This agent also induces NMDA-receptor–mediated receptor currents in the hippocampus, which is important for learning and memory.
34 In vitro studies also show that TBPB decreases the processing of APP into β-amyloid
34—an effect similar to that produced by previous M1 agonists. The allosteric agonist BCQA produces no direct agonist activity, but it shifts the dose-response for acetylcholine on M1 receptors. It is systemically active and reverses cognitive impairment induced by scopolamine.
35
The allosteric agonists may provide a highly selective means of activating M1 receptors. This area of research continues to be developed. Some of these drugs, if they directly activate G protein–mediated signal transduction, may overcome the problem of M1 receptor uncoupling, which has been shown to occur in Alzheimer disease and which may limit the effectiveness of orthostatic muscarinic agonists.
36-39