Acetylcholine receptors

The neurotransmitter acetylcholine (ACh) mediates its effects in the peripheral and central nervous systems through two distinct families of receptors, the muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). The five mAChR subtypes m1-m5 are G-protein coupled receptors coupled to intracellular second messenger cascades, whereas the nAChRs are pentameric ligand-gated ion channels arising from homomeric and heteromeric assemblies of α, β, δ, ε and γ subunits. Both classes of ACh receptors are involved in a wide range of physiological functions, and ligands targeted at mAChRs and nAChRs have over the years attracted considerable interest as potential therapeutics in the treatment of pain and numerous neurodegenerative and psychiatric disorders.

During the 1980s and 1990s the NeMe group developed series of novel mAChR agonists bioisosterically derived from arecoline (a constituent of areca nuts) and norarecoline. In recent years our medicinal chemistry efforts have been focused on the neuronal nAChRs. Using the prototypic mAChR agonist carbachol as a lead, a series of 3-(N,N-dimethylamino)butyl-carbamate analogs have been synthesised. The compounds are potent nAChR agonists displaying high degrees of selectivities for neuronal nAChRs over mAChRs. Furthermore, some of the compounds exhibit pronounced selectivities for α2-containing over α4-containing nAChR subtypes. These findings are currently being explored further with the synthesis and pharmacological characterisation of new series of analogs.