Muscarinic receptor agonists in Alzheimer's disease more than just symptomatic treatment?

Abstract

Research into and development of selective muscarinic receptor agonists for the treatment of Alzheimer's disease is based on the 'cholinergic hypothesis' of the disease. This implies that cholinergic replacement therapy might be beneficial in alleviating some of the cognitive dysfunctions associated with the disorder. Muscarinic M(I) receptor-selective agonists may be effective in the treatment of Alzheimer's disease, regardless of the extent of degeneration of presynaptic cholinergic projections to the frontal cortex and hippocampus. In this context, such compounds represent a more rational treatment for Alzheimer's disease than the cholinesterase inhibitors. However, disappointing clinical results have been reported with some muscarinic agonists in patients with Alzheimer's disease. This may be due to a lack of selectivity for M1 receptors (as is the case with milameline), low intrinsic activity (Lu 25109), very low bioavailability and extensive metabolism (xanomeline), and a narrow safety margin [all of the abovementioned drugs and sabcomeline (SB 202026)]. Recent studies indicate a relationship between the formation of β-amyloid plaques and neurofibrillary tangles and the loss of cholinergic function in the brains of patients who had had Alzheimer's disease. A cholinergic hypofunction in Alzheimer's disease can be linked to the formation of neurotoxic β-amyloids, which can further decrease the release of acetylcholine (a presynaptic effect) and impair the coupling of M1 receptors with G-proteins (a postsynaptic effect). This uncoupling leads to decreased signal transduction, impairments in cognition, a reduction in the levels of trophic-secreted amyloid precursor proteins, the generation of more neurotoxic β-amyloids and a further decrease in acetylcholine release. This 'vicious cycle' may be prevented, in principle, by M1-selective agonists. These new findings raise the exciting prospect that future M1 agonists may be useful both as symptomatic treatments (e.g. to treat cognitive and behavioural symptoms) and as disease- modifying agents in Alzheimer's disease.