[Selective M1 muscarinic agonists: failure of therapeutic strategy against Alzheimer's disease or inappropriate tactics?]

Abstract

Clinical trials of selective M1 muscarinic agonists against Alzheimer's disease (AD) were, except perhaps for xanomeline, decevant. However, the strategy sustaining the conception of these agonists was rational: based on the high densities of post-synaptic M1 and M2/M3 receptors, respectively, in the brain (cortex, hippocampus) and periphery as well as on the preservation of M1 receptors in the AD. However, most of the clinically tested M1 agonists exhibited low (but suffisant for pre-synaptic M2 autoreceptors and M3 heteroreceptors on the glutamatergic terminals) M2/M3 agonisms, susceptible to annul their M1 agonism. The rest of these agonists, developed a M1 agonism too weak, susceptible to operate as functional antagonism in the cholinergic synapses. In conclusion, it appeared that the efficacy of the M1 agonists against AD must be tested with full M1 agonists being also net M2/M3 antagonists, a profile recently evidenced with tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanemethanamine (AE14).