Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors

Improved understanding of how brain function is altered in neurodegenerative disease states, pain and conditions, such as schizophrenia and attention deficit disorder, has highlighted the role of nicotinic acetylcholine receptors (nAChRs) in these conditions and identified them as promising therapeutic targets. nAChRs are widely expressed throughout the peripheral and central nervous system, and this widespread nature underlines the need for new ligands with different selectivities and pharmacological profiles if we are to avoid the adverse side effects associated with many of the nAChR modulators currently identified. Partial agonists have the unique property of being able to act both as agonists or antagonists depending on the concentration of endogenous neurotransmitter. Moreover, the agonist action of partial agonists has a ‘ceiling’ effect, giving them a large safety margin and making them an attractive proposition for therapeutic molecules. Partial agonists of nAChRs are currently being developed as a nicotine replacement therapy for smoking cessation and for the treatment of a number of neurological diseases associated with a loss of cholinergic function. This commentary will discuss the pharmacological properties of partial agonists and review recent research developments in the field of partial agonists acting at nicotinic receptors.