Design and discovery of neuropeptide Y-1 receptor antagonists

Neuropeptide Y (NPY) has been the focus of much attention since its discovery as the most abundant peptide in mammalian brain. It has been implicated in many roles in both the periphery and the CNS. The first cloned receptor subtype, Y-1, has been identified as an important mediator for many of these effects. Potent, selective Y-1 receptor antagonists have been developed and have certainly helped clarify the peripheral roles of NPY and the receptors involved. However, there is still a need for Y-1 antagonists that can be administered peripherally, even orally, and penetrate the CNS. Such compounds would help define the roles of NPY and Y-1 receptors in the CNS, an area rich in potential for novel drug therapy.