Pharmacology of Hypocretin/Orexin Peptides and Small Molecules

Despite their relatively recent discovery in 1998, the hypocretins (also known as orexins) and their receptors are already the focus of several investigations as sites for therapeutic intervention in a number of endocrinological and neurological disorders. The rapidity with which the hypocretin system has been adopted as a high-interest target is mainly the result of an accumulation of compelling evidence from in vivo studies showing that the hypocretins regulate a number of aspects of physiology and behavior, especially those involved in sleep, arousal, and energy homeostasis. High-throughput screening efforts by a number of pharmaceutical companies have now identified novel small molecules that interact potently and specifically with the hypocretin receptors. Despite these considerable efforts, very little is known regarding the structures of the receptors, their endogenous ligands, the molecular basis of their interactions, or the signaling pathways they use. For example, no attempt has been made through receptor mutagenesis, or by any other means, to define the key interactions that occur between the receptors and the endogenous peptide ligands. Although such studies are likely to be ongoing within pharmaceutical companies with active hypocretin receptor drug discovery programs, the information available to the general scientific community remains very limited. This chapter reviews what is currently known about the molecular pharmacology of this system, focusing on the structures and activities of the peptides and some of the small molecules for which published biological data exist.