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

ABSTRACT

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.

KEYWORDS:

• Allosteric sites
• multitarget
• nicotinic acetylcholine receptors
• nAChRs
• orthosteric sites
• polypharmacology

Article highlights

• The multifactorial origin of complex diseases is well accepted and there is increasing consensus that pharmacotherapy requires multitargeted strategies.

• Polypharmacology, which refers to the ability of a molecule to simultaneously interact with multiple target proteins, offers a reasonable conceptual framework to overcome some of the hurdles that have characterized drug discovery in the last decade.

• Nicotinic acetylcholine receptors (nAChRs) possess numerous ligand binding sites (the orthosteric site and allosteric sites). There are several examples of therapeutically useful and investigational drugs, which act through simultaneous interactions with different targets and orthosteric or allosteric nAChRs binding sites.

• Among other strategies, the analysis of the characteristics of both available promiscuous molecules and therapeutically useful drug combinations is a straightforward route to guide the design of novel polypharmacological agents

• The multiple allosteric sites present in nAChRs exhibit an ample variety of shapes, sizes, physicochemical properties and ligands. These characteristics offer an unusual opportunity for exploring the chemical space in the search of druggable molecules that could fit and interact at these cavities.

• This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank Dr. B. K. Cassels and Dr. P. Möller for critical reading of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors are funded by FONDECYT Grants 1130185 (to M Reyes-Parada) and 1150615 (to P Iturriaga-Vasquez)