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.

A novel series of dimeric 2-[4-(3-aminopropoxy)phenyl]benzimidazole dopamine (DA) D3 receptor antagonists has been discovered. Most of the dimeric structure is needed for DA binding activity; however, a second basic nitrogen atom is not required. A representative compound had no effects on DA synthesis in rat brain but inhibited spontaneous locomotor activity in mice and stimulated locomotor activity in habituated rats.

A novel series of 2-[4-[3-(4-aryl-1-piperazinyl)propoxy]phenyl]benzimidazole dopamine D3 receptor agonists has been discovered, The aryl group was crucial for activity and Topliss analysis confirmed that phenyl was optimal for DA D3 receptor binding and selectivity, The phenyl analogue 3 was a partial agonist in a second messenger assay, It increased DA synthesis in rat brain and inhibited exploratory locomotor activity in rodents.