Introduction: Nicotinic acetylcholine receptors (nAChRs) have been extensively studied because of their importance in physiological processes and their involvement in a number of muscle and neuronal human pathologies. However, the role of specific subtypes remains poorly understood due to the lack of selective nAChR probes. During the last decade, drug design strategies have been powered by a wide variety of natural compounds with diverse chemical structures, and by the structural characterization of several nAChRs structural homologs.
Areas covered: In this review, the authors present a short overview of nAChRs, and some natural sources of bioactive molecules targeting these receptors. The authors provide an emphasis on α-conotoxins from Conus venoms, which provide the most diverse selective antagonists of nAChRs known to date, as well briefly discussing macrocyclic imine toxins. The authors, furthermore, review valuable radioactive and non-radioactive methods used for discovering novel ligands targeting nAChRs and highlight high-throughput developments in receptor-binding and electrophysiological assays. Finally, the authors review the molecular modeling approaches used in the last few years with an aim to provide an overview of their potential to identify and optimize selective nAChR ligands.
Expert opinion: Recent years have provided new valuable techniques for the detection and identification of new nAChRs ligands, along with an increasing use of different molecular modeling tools. This furthering of knowledge has had an impact on the design and discovery of more potent and selective nAChRs ligands. There is still however a lack of high-resolution structural information that will require new developments.