The development of novel polypharmacological agents targeting the multiple binding sites of nicotinic acetylcholine receptors.

Introduction: Polypharmacology, which refers to the ability of a molecule to simultaneously interact with multiple target proteins, is shifting the drug discovery process from a 'one-drug-one-target' paradigm to a conceptual framework in which the multitarget profile of small molecules is proactively pursued. Nicotinic acetylcholine receptors (nAChRs) appear as attractive targets for the design of polypharmacological agents. These proteins participate in the regulation of multiple physiological processes and impressive progress has been made regarding their structure and function. Moreover, they contain several ligand binding sites, and a number of compounds including orthosteric and allosteric ligands, have been described.

Areas Covered: The authors provide an overview of some of these topics and briefly discuss the mechanisms of action of some known promiscuous drugs that act at nAChRs, with the idea that this analysis will serve to guide the development of novel polypharmacological agents with a wide spectrum of actions.

Expert Opinion: The authors anticipate that many innovative drugs will be compounds intentionally designed to have polypharmacological properties. Furthermore, the authors suggest that although the search for multitarget drugs acting at the orthosteric site of nAChRs will remain an interesting option, allosteric sites of these receptors exhibit a much greater polypharmacological potential.