Long before we understood biochemical and molecular activities of GPCRs, humans used the natural products belladonna, ergot and opium from a variety of plant sources to elicit pharmacological effects at then unknown targets to treat a number of maladies. It was not until the beginning of the twentieth century that the idea of receptors was conceived when Paul Ehrlich proposed that drug substances could interact with discrete "chemoreceptors" and produce pharmacological effects. Other prominent pharmacologists including Henry Dale, Otto Loewi, R.P. Ahlquist, and James Black were instrumental in describing the actions of compounds at receptors later identified as GPCRs, laying the foundation for rational drug design.

The advent of molecular biological approaches led to the identification of the GPCR superfamily of approximately 750 genes comprising roughly 1% of the genome.1 However, the functions and endogenous ligands of a large number of these receptors (orphan GPCRs) remain to be elucidated (see Chapter 16). The cloning of GPCRs has produced a significant impact on drug discovery, leading to the biomolecular identification of both the genes and proteins of those receptors previously described pharmacologically (e.g., those for biogenic amines), additional isoform subtypes of such receptors, and novel, previously uncharacterized GPCRs whose functions are just now being deciphered and for which drugs are being developed. Whereas other chapters in this book deal specifically with a number of therapeutic areas of GPCR drug discovery, this chapter reviews some of the more general and critical aspects of drug discovery research, ranging from target validation to the end result: the synthesis of a drug that interacts selectively with a GPCR target to elicit a therapeutic effect.

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