Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists.

The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK(1)) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration.

RO-10-5824 is a selective dopamine D4 receptor agonist that increases novel object exploration in C57 mice.

Novelty seeking as a behavioral phenomenon emerges as a compromise between approach and avoidance behavior. Although novelty seeking is thought to play a role in drug abuse and in cognition, the biological basis for this construct is poorly understood. At a genetic level, dopamine D4 receptors (D4R) appear to be critical for the behavioral expression of novelty seeking.