Orphan Gpcrs In The Central Nervous System

The successful history of CNS drugs targeting GPCRs led to interest in quickly identifying orphan GPCRs with promise as new drug targets. There are approximately 100 GPCRs, identified by sequence homology and predicted 7-transmem-brane (7TM) domain topology, for which endogenous ligands have not been iden tified that are known as orphan GPCRs. Although most of these GPCRs are expressed widely in the CNS, the future impact of orphan GPCRs on CNS drug discovery is a subject of debate.195,196

Researchers are in agreement that increased knowledge of physiology, including new signaling systems involving GPCRs, will ultimately result in new medications, but it is difficult to predict the timeframes required. Certain recently deorphanized receptors such as the orexin receptors were validated rapidly as drug targets for the treatment of CNS disease. Orexin receptors OX1R and OX2R were deorphanized in 1998 by identifying the components of a rat brain extract that activated the receptors in a screening assay, peptides now known as orexin-A and orexin-B.197

These peptides were initially shown to exert activity in appetite control, but orexin-knockout mice soon displayed disrupted sleep patterns similar to narcolepsy.198 At the same time, positional cloning in a narcoleptic dog colony revealed that the canarc-1 gene corresponds to the orexin B receptor.199 The autosomal recessive canarc-1 mutation in Doberman pinschers and Labrador retrievers produces narcolepsy that is pharmacologically and physiologically validated with the human condition. The easily detectable activity of orexin peptides has substantiated interest in their receptors as potential CNS drug targets. However, other GPCRs with unknown or less well-characterized ligands represent major challenges for drug discovery.200

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