Current and future trends in drug discovery and development related to nicotinic receptors

Abstract

The potential of nicotinic acetylcholine receptors (nAChRs) as therapeutic targets has evolved over the last 50 years. First focused on peripheral, muscle and ganglionic, therapeutics, it evolved toward more CNS focus, mainly thanks to the identifi cation and cloning of various CNS nAChRs. A minimalistic approach was initially taken to identify drugs that worked on recombinant versions of the two main CNS nAChRs: the homomeric * 7 and the heteromeric * 4 β 2 . From the early 1990s to the present, selective * 4 β 2 agonists and modulators have been discovered. In the last decade highly selective a 7 agonists and positive allosteric modulators (PAMs) have emerged. Unfortunately, success in the clinic has been limited. Improved understanding of the molecular nature of drug-receptor interactions, molecules with optimized pharmaceutical properties, biomarkers that refl ect pharmacodynamic and clinical benefi t, and foundational understanding of the underlying disease physiopathology are all needed for delivering the new nicotinic drugs of the twenty-fi rst century. We here review advances in some of these areas, summarizing the growing evidence that CNS nAChRs represent a family of receptors with signifi - cant roles in human diseases and a strong potential for delivering much needed therapies to patients with unmet medical needs.