Muscarinic M1 receptor agonists and M2 receptor antagonists as therapeutic targets in Alzheimer's disease

Alzheimer's disease is the most common form of senile dementia and is of increasing medical and economic importance. One of the earliest findings in the systematic study of Alzheimer's disease was the progressive loss of acetylcholinergic neurons. This lead to the so-called cholinergic hypothesis of Alzheimer's disease and provoked a search for cholinergic replacement therapies. This has resulted in compounds capable of inhibiting the catabolism of acetylcholine (acetylcholinesterase inhibitors) being licensed for the treatment of Alzheimer's disease. However, the search for directly acting, selective, muscarinic M-1 receptor agonists and M-2 receptor antagonists, that are capable of increasing acetylcholine levels in the neocortex, has not yet proved successful. For the muscarinic agonists this failure has been largely due to the difficulty in finding genuinely selective compounds. As a result, there has been a reduction in the number published patents in this area. This review discusses the rationale, progress and the possible future for these two potential approaches to the therapy of Alzheimer's disease especially in light of some recent patents containing selective compounds.