Ian A. McDonald, Jean-Michel Vernier, Nicholas Cosford and Janis Corey-Naeve Pages 357 - 366 ( 10 )
In contrast to the considerable effort over many years to design agonists of the muscanmc acetylcholine receptor, until recently little attention has been directed towards agonists of the nicotinic family of acetylcholine receptors (NAChRs). Nevertheless, the structure and function of NAChRs has been a topic of intense research for several decades. Currently available NAChR agonists were discovered either as natural products or have been the result of limited structure-activity relationship studies based on natural products. These agonists were initially identified in classical ligand binding assays and characterized by various in vitro and in vivo models using rodents or rodent tissue preparations. Recent advances in the molecular biology of NAChRs have allowed the generation of stable cell lines expressing recombinant human NAChRs. The incorporation of the .e cell lines into high throughput functional screening assays has stimulated the search for novel, subtype selective NAChR agonists which should have therapeutic utility for the treatment of a number ofCNS disorders, such as Alzheimer's disease, Parkinson's disease, attention deficit disorder and schizophrenia. Some of these agents, for example SIB-1508Y, ABT-418 and DMXB (GTS 21), are presently helping to establish the clinical utility of nicotinic agonists in these diseases. This review focuses on the molecular biology of NAChRs, the development of cell-based functional assays, and the use of these assays to critically support structure-activity relationship studies of two series of compounds from our own laboratories.