Strategies for the Development of Selective Serotonergic Agents

Abstract

Many of the ligands in use today to investigate serotonin receptors and serotonin receptor pharmacology were serendipitous discoveries; this includes ligands that are commonly regarded as being "selective" for a given population of serotonin receptors. Nevertheless, there still remains a number of serotonin receptor types that lack a truly selective ago-nist and/or antagonist. Over the past 20 yr, there have been various attempts to rationally develop ligands with greater selectivity, or selective ligands for serotonin receptor types for which such agents were lacking. To this end, we describe some of our efforts to develop selective serotonergic agents by presenting a series of case studies. Several different strategies have been employed to achieve this goal. In particular, the "deconstruction-reconstruction-elaboration" approach is shown to be useful for aiding the development of selective ligands where a lead structure is already known, and the utility of the "standard series" approach is illustrated where a lead structure is not known. The discussion is focused on these and other methods that could have general applicability for the development of other selective serotonergic and nonserotonergic agents.